Tái Tạo Thể Tích Khuôn Mặt Bằng Filler – Kyle K. Seo (2021)

236
4.17.1 Pretreatment Assessment
As a preliminary matter, it is essential first to
ascertain whether the disease is still in progress or
has been treated. Redness in the skin suggests
ongoing inflammation, in which case treatment
with HA filler should be postponed until a later
time [40]. It is necessary to clarify whether the
patient is still on medication or has completed the
required drug therapy. To the extent the patient has
undergone a complete course of acute-phase treat-
ment, with no further progression of symptoms
during the subsequent months, HA filler treatment
may be attempted even where the patient is still
undergoing maintenance procedures. Palpate the
depression with the finger to estimate the degree
of adhesion and  the likely treatment outcome
based on the hardness of the overlying tissue.
Severely adhered or tethered down tissue can be
very hard to treat, which should be clearly com-
municated to the patient in advance. Regarding
the estimated injection volume; as a general rule
of thumb, adhered or bound-down tissue requires
a larger amount of HA filler compared with nor-
mal tissue to provide lifting. Areas such as the
anterior cheek (buccal cheek) also tend to con-
sume a larger-than-­expected amount of product
due to the absence of underlying bony structure to
support the tissue from below.
4.17.2 Injection Technique
It is advisable to use monophasic or biphasic HA
with good high viscoelasticity that can withstand
the pressure exerted by the tough, hard scar tis-
sues in the treatment area. The use of a cannula is
advised over a needle to minimize inadvertent
Fig. 4.124  (a) Morphea, (b) Linear scleroderma, (c) Before and (d) after fller volumization for morphea
c
d
a
b
4  Regional Particulars

237
injection of HA filler into blood vessels adhered
to the depressed tissue. It is also recommended to
use cannulas sized 23G or thicker, as thinner can-
nulas can be too pliant and may bend under the
force of the tough fibrous tethering. The cannula
entry point is created 1 cm lateral to the border of
the depressed scar along its longitudinal axis.
Achieving full elevation of the depressed tissue
with HA can be elusive where severe adhesions
are present. In such case, another alternative is to
combine subdermal filling with the subcision
technique to release the tethered tissue away
from the deeper layers before placing a layer of
HA filler underneath [41].
The procedure can be highly painful, owing to
the tight adhesions in the tissue. Accordingly, it is
advisable to inject a small amount of lidocaine in
the treatment area in advance, since numbing
creams alone may be insufficient to provide nec-
essary numbing. Sedation may be considered
where soft tissue depressions are prevalent across
broad areas of the face with tight adhesions to the
deeper structures.
4.17.3 Complications
Elevating the tissue can be a challenge in areas
where severe adhesions are present, as the tightly
bound scar tissues would push the injected HA
filler away into surrounding normal tissue, caus-
ing surface irregularities. Further, blood vessel
perforation and bruising may occur even with the
use of cannulas in areas with tissue adhesion.
Bruising is a common occurrence, particularly
where the subcision technique is used.
4.18
Facial Asymmetry Correction
Difficulty
Level:
A,
Effectiveness:
A,
Complications: B
Symmetry constitutes an essential element of
a beautiful face. Facial symmetry can be dis-
rupted, however, by a range of different factors,
the correction of which requires orthodontic or
even surgical interventions including upper and
lower jaw surgery in severe cases. That said,
moderate improvements in facial asymmetry can
be achieved with HA fillers by building up vol-
ume on the weaker side of the face and restoring
the alignment of the canted maxilla/mandible
[42] (Fig. 4.125). Facial asymmetry can be either
congenital or acquired, and can be broadly
divided into those caused by skeletal discrepan-
cies and those stemming from soft tissue
­problems between the left and right face. Skeletal
discrepancies comprise hemifacial hypoplasia,
hemifacial microsomia, hemifacial hyperplasia,
maxillary canting, mandibular deviation, and
hemimandibular hypoplasia. Soft tissue  prob-
lems include imbalance of masseter muscles
caused by the habit of chewing on only one side,
asymmetrical sagging of the face with aging, dis-
crepancy in the volume of malar fat pad or buccal
fat pad on each side, or the rare incidence of pro-
gressive hemifacial atrophy also known as the
Parry-Romberg syndrome [43]. Facial asymme-
try may also be caused by injury or trauma or
more recently by increased incidences of botched
cosmetic procedures involving soft tissue fillers,
autologous fat, liposuction or thread lifts.
Successful correction of facial asymmetry with
HA filler is premised on the proper pretreatment
evaluation of the underlying cause and indica-
tion, as well as the feasibility of treatment with
Summary 1: Moderate improvement in
facial asymmetry can be achieved by bal-
ancing out the volume deficit on one side of
the face and realigning the canted mandible
leveraging the volumizing effect of HA
filler.
Summary 2: The facial midline extending
inferiorly from the upper face intersected
by a horizontal line connecting the left and
right pupils can be used to identify the pres-
ence of facial asymmetry and midline dis-
crepancy on the frontal image.
Summary 3: To restore the facial summetry, it
is necessary to create a new soft tissue gna-
thion (Gn’) that is aligned with the midline of
the upper face and to build volume on the
smaller side of the chin.
4.18  Facial Asymmetry Correction

238
Fig. 4.125  (a, c, e) Before and (b, d, f) after correction of asymmetry with HA filler and botulinum toxin
a
b
c
d
4  Regional Particulars

239
HA filler. Also, when volumizing the smaller side
with HA to balance facial symmetry, it must be
born in mind that simply mirroring the large side
to achieve perfect symmetry can lead to an unnat-
ural and overly large face or chin.
4.18.1 Pretreatment Assessment
While the use of medical imaging such as X-ray
or CT of the underlying facial bony structure can
offer a more accurate diagnosis, clinical photo-
graphs alone can be useful for determining facial
asymmetry before treatment [44]. As a prelimi-
nary step, it is helpful to draw the facial midline
on the patient’s frontal face image extending
inferiorly from the upper face, followed by a hor-
izontal line connecting the left and right pupils
(Fig. 4.126). Significantly, the interpupillary line
is known to remain parallel to the floor  even
where facial asymmetry is present.
Using these lines as the reference, start by
assessing the contour asymmetry between the left
and right face in the upper, mid, and lower seg-
ments. Specifically, on the upper face, evaluate
the bilateral symmetry in the frontal bone,
recessed temples, superciliary arches, and brow
height. On the mid-face, compare the size and
height of the malar fat pad, malar eminence, and
zygomatic arch on each side. On the lower face,
examine the differences in buccal hollows, jowl
sagging, masseter size and chin symmetry
between the left and right face.
Next, assess whether or not the facial midline
has been shifted to one side. More specifically,
check for the presence of any nasal deviation in
the midface or a chin deviation in the lower face.
The nose is deviated if the glabella-subnasale line
e
f
Fig. 4.125  (continued)
4.18  Facial Asymmetry Correction

240
Fig. 4.126  Pretreatment assessment of facial asymmetry ((a) Before, (b) after treatment using fller and botulinum
toxin and (c) assessment and treatment strategy for facial asymmetry)
a
c
b
4  Regional Particulars

241
is off to the midline of the upper face. This devia-
tion to one side is caused primarily by a canted
maxilla or hemifacial hypoplasia, that is, unilat-
eral underdevelopment of one side of the maxilla.
Patients with a maxillary cant tend to present not
only a deviated nasal dorsum but also a tilted lip
line. On smiling, they display an uneven show of
upper teeth and gum between the left and right
sides of the maxilla (Fig. 4.116). A maxillary cant
is usually accompanied by chin deviation where
the mandibular midline gravitates to one side. A
chin deviation is identified when the subnasale-­
to-Gn’ line is out-of-sync with the facial midline
while the midline of the midface is in proper
alignment. Patients with chin deviation demon-
strate unilateral underdevelopment of the man-
dibular body or ramus on one side, with the Gn’
tilted toward the smaller side of the mandible.
Meanwhile, facial depressions caused by trau-
matic injuries or facial asymmetries resulting
from botched aesthetic procedures can also be
improved moderately by adding HA filler to the
side where volume is deficient. Note, however,
that full correction of the depression/misalign-
ment is elusive where scar tissue adhesions are
present beneath the skin. Where the facial asym-
metry is the result of an incorrect volume aug-
mentation procedure where too much HA or fat
was placed on one side resulting in an uneven
outcome, hyaluronidase or fat reducing injection
is required to reduce the excess volume.
4.18.2 Principles and Injection
Technique for Facial
Asymmetry Correction
The cardinal principle in correcting facial asym-
metry with HA filler, regardless of the underlying
cause, is to build up volume on the smaller side
and to restore facial alignment, where necessary,
by readjusting the midline of the chin (Fig. 4.127).
Regarding the volume restoration, HA filler can
be applied to improve asymmetry between the
left and right forehead or temples by enhancing
the volume on the smaller side in the upper face.
In the midface, asymmetry between the bilateral
malar eminence and zygomatic arches can be
balanced out by augmenting volume on the
smaller side. Note, however, that achieving per-
fect symmetry with the larger zygoma is neither
necessary nor desirable in Asians who generally
disfavor having a prominent zygoma. In the lower
face, restoring the anterior (submalar) and poste-
rior (subzygomatic) cheek and strengthening the
jawline and chin of the smaller side can
help  resolve the  asymmetry  to some extent.  In
patients with a tilted lip line due to a maxillary
cant, lip filler would be also helpful for restoring
facial symmetry (Fig. 4.127).
Meanwhile,
restoring 
facial
symmetry
through  readjusting the midline of the devi-
ated  chin is a  prerequisite process for facial
asymmetry correction. In order to correct a chin
deviation, it is necessary to create a new soft tis-
sue Gn (Gn’) that is aligned with the midline of
the upper face, while enhancing volume on the
smaller side of the chin to restore the facial sym-
metry. Caution must be taken against overfilling
the smaller side of the chin to match the larger
side as it may serve only to create a chin that is
overly broad. In patients with a Class III maloc-
clusion (prognathia) or a notably bulky chin, it
may be preferable to forgo correction of chin
deviation (see Sect. 4.14).
4.18.3 Combination Treatment
During the augmentation it is advisable to con-
currently slim down the contralateral side of the
face (i.e., the larger side) with BoNT-A injections
in the masseter m. and fat-reducing injections in
the sagging jowl. Meanwhile, in order to fix the
bilateral difference in jowl sagging, it is neces-
sary to undertake thread-lifting procedures on the
areas concerned in addition to fat-reducing injec-
tions. In patients with an uneven gum display or a
tilted lip line due to a maxillary cant, the treat-
ment may be combined with injection of 3 U of
BoNT-A for mouth corner elevation in the
downward-­tilting side (Fig. 4.128), or conversely
with 1–2 U of BoNT-A in the zygomaticus minor
muscle of the upward tilting side (Fig. 4.129).
4.18  Facial Asymmetry Correction

242
Fig. 4.127  Injection technique for the correction of facial asymmetry using filler and botulinum toxin ((a) Before, (b)
after treatment, (c) assessment and treatment strategy for facial asymmetry)
a
b
c
4  Regional Particulars

243
Fig. 4.128  Botulinum
toxin (3U)
injection point for mouth
corner elevation
Fig. 4.129  Botulinum
toxin injection point for
relaxing the zygomaticus
minor m
4.18  Facial Asymmetry Correction

244
4.19
Neckline Treatment with HA
Filler
Difficulty
Level:
B,
Effectiveness:
B,
Complications: B
Occasionally, people may present with a visi-
bly wrinkled neck that is not congruent with their
smooth youthful-looking faces that have been dil-
igently maintained with the regular use of
BoNT-A, injectable fillers, and energy-based
devices. The skin of the neck is thinner than on
the face and ages more easily, while the frequent
movement of the platysma muscles in this area
makes the neck skin more prone to wrinkling as it
loses elasticity with age. Moreover, the neck is an
area often missed with sun protection even
though it is exposed to the sun as frequently as
the face. It is for this reason that necklines are
metaphorically referred to as “the tree rings of a
woman,” that reveal her age as does the dorsum
of the hand.
Necklines can largely be divided into horizon-
tal necklines, vertical bands (platysma banding),
and crépey fine wrinkles of the neck. Horizontal
necklines are a congenital feature present from
birth together with other horizontal flexion creases
of the body such as those found in the wrists and
finger joints. Anatomically, the horizontal lines of
the neck are formed by the attachment of the
fibrous septa (underlying these rhytides) vertically
to the muscles below. The rhytid depth progres-
sively increases with age due to the increased
deposition of subcutaneous fat in the adjacent tis-
sue. Meanwhile, vertical necklines, often referred
to as platysmal banding, develop due to the
repeated contraction of platysma muscles during
speaking or mobilization of the perioral muscles
[45] (Fig.  4.130). Platysma bands run vertically
from under the jawline to the clavicle and tend to
appear more prominently in thin people with
reduced body weight and little soft tissue to cover
the underlying muscle contraction. Coupled with
excess skin or submental fat under the chin, platys-
mal banding can give rise to the appearance of a
“turkey neck” or “gobble neck deformity” com-
monly found in elderly Caucasians. Finally, crépey
fine wrinkles of the neck occur due to the natural
loss of skin elasticity with aging, and typically
appear anterior to the thyroid cartilage or trachea
during the swallowing of food or the movement of
the neck (Fig. 4.130).
4.19.1 Pretreatment Assessment
It is important first to clarify precisely which of
the three different types of neck wrinkles (i.e.,
horizontal/vertical lines, or crépey neck skin) the
patient wishes to address [45]. To add a caveat,
however, the neck can be a tricky area to treat in
each of these indications. Unlike facial wrinkles,
treatment of necklines is usually not a single,
one-off process, often requiring multiple treat-
ment sessions with the associated downtime from
bruising and surface irregularities, while deliver-
ing modest improvements; such aspects must be
conveyed in full to the patient before treatment.
4.19.2 Injection Technique
Horizontal necklines are congenital structures
that cannot be eradicated completely. For what it
is worth, however, moderate improvements can
be achieved by filling the etched-in horizontal
creases that deepen with age from the deposition
of subcutaneous fat in the adjacent tissue [46]
(Fig. 4.131). Regarding the choice of HA filler, it
Summary 2: Horizontal necklines can be
improved  to some extent by filling the
etched-in horizontal creases using 30-G,
33-G needle and a 27-G cannula. Soft mono-
phasic HA fillers with high spreadability is
recommended.
Summary 3: Crépey fine wrinkles of the
neck can be improved to some extent with
hydrolifting treatment using HA to restore
skin elasticity and firmness in the neck.
Summary 1: Necklines can largely be
divided into horizontal necklines, vertical
bands (platysma banding), and crépey fine
wrinkles of the neck.
4  Regional Particulars

245
Fig. 4.130  Platysma bands (a) before and (b) 2 weeks after 50 U of botulinum toxin injection per side, (c) crépey fine
wrinkles of the neck
a
c
b
is recommended to use soft flexible monophasic
HA fillers such as Belotero® Soft with high
spreadability (Table 4.18). In the author’s experi-
ence, Restylane® Vital is effective for filling the
creases due to its good elasticity  while requir-
ing much less amount of product but are more
likely to leave the appearance of bumps on the
surface; in contrast, thinner products such as
Belotero® Soft cause much less irregularity owing
to its more fluid and cohesive property but involve
4.19  Neckline Treatment with HA Filler

246
a higher risk of bruising. The target plane of
injection is the deep dermis/subdermal plane.
Where bruising must be avoided as a priority, it is
advisable to use a 27-G cannula to fill the etched-
­in horizontal creases in the subdermal layer using
the retrograde linear threading technique. Where
the patient is willing to tolerate some degree of
bruising, it is preferable to use a 30-G needle
both in the deep dermis and the subdermal layer
to fill the grooves based on the retrograde linear
threading technique. While the needle is more
effective for filling in the etched-in creases, care
must be taken as utilizing a needle entails a
higher risk of bruising and bumpiness.
Meanwhile, the best strategy for treating the
vertical platysmal bands is to relax the platysma
m. with BoNT-A.  It is recommended that
20–30  U of BoNT-A is injected per side to a
total of 50–60 U per session [45]. While a touch-
up may be administered 2 weeks following the
initial treatment, caution is advised as an over-
dose of BoNT-A in the platysma band may cause
complications such as hoarseness, dysphagia, or
exacerbation of cervical disc herniation due to
the weakening of the cervical neck muscles. In
addition, considering that the primary indication
of BoNT-A injections is for the treatment of
dynamic lines and wrinkles appearing upon
facial animation, patients with excess fat (i.e.,
double chin) or loose skin or under the chin can-
not be treated satisfactorily with the use of
BoNT-A injections in the platysma bands alone.
In such case, BoNT-A should preferably be
combined with fat reducing injections or lipo-
suction to address the excess submental fat,
while combination with HIFU, thread-lifting, or
facelift surgery is advised for tightening or repo-
sitioning the loose excess skin hanging under the
chin,
Finally, crépey fine wrinkles of the neck can
be effectively treated with hydrolifting treatment
with HA to restore skin elasticity and firmness in
the neck (see Sect. 4.20). For a more even distri-
bution of HA filler, the use of injector devices or
Mirajet® system is advised over manual injection.
It is recommended to inject 1–2  mL of a soft
monophasic HA filler with good cohesivity such
as Belotero® Soft evenly across the entire neck
[47]. A top-up procedure may be repeated
1  month later, if necessary. For better results,
hydrolifting can be combined with skin booster
Table 4.18  Summary of horizontal neck line injection
technique
Item
Contents
Needle vs. Cannula
30-G, 33-G needle
27-G cannula where bruising
must be avoided
HA filler
Monophasic HA filler with
light
Viscoelasticity for thin skin
Amount of HA filler
less than 1 mL per session
Depth of injection
Deep dermis and subdermal
layer
Target area
deep horizontal crease 
Anesthetics
Topical anesthetics for more
than 40 mins
Nondominant hand
Hold the skin to maintain skin
tension
Fig. 4.131  (a) Before and (b) after treatment of horizontal necklines with HA fillers
a
b
4  Regional Particulars

247
injections or Fraxel® laser or Thermage® radio
frequency devices to help build skin elasticity
and make the neck look more refreshed.
4.20
Hydrolifting (Multiple
Intradermal Injections of HA
Filler)
Difficulty
Level:
B,
Effectiveness:
A,
Complications: B
The effects of HA filler injection can be con-
sidered as three-fold: It serves to replace lost vol-
ume (“space-filling effect”), restore skin elasticity
(“structure stabilizing effect”), and stimulate cell
regeneration (“cell-stimulating effect”). Space-­
filling effect refers to the volumizing effect of
HA filler to lift etched-in grooves and plump
facial depressions by literally “filling out” the
areas of volume depletion. Structure stabilizing
effect describes how HA filler restores skin elas-
ticity and firmness by reintroducing HA, a natu-
rally occurring substance responsible for skin
elasticity, directly into the dermis to replenish the
age-related decrease in HA.  Cell-stimulating
effect describes how the injection of HA in the
dermis can boost collagen and elastin production
via fibroblast activation [48, 49]. Not only does
this help improve skin elasticity but it also allows
the rejuvenation effect to persist beyond the lon-
gevity of the underlying HA filler. Among these,
hydrolifting leverages the structure stabilizing
and cell-stimulating effects of HA filler to restore
skin elasticity. At the same time, it harnesses the
hydrophilic nature of HA to draw  water up
to1000 times its molecular weight to rehydrate
the skin. According to Kerscher et  al. [50],
marked improvements were reported in skin elas-
ticity and skin surface roughness 24 weeks after
administration of  hydrolifting, while Distante
et al. [45] reported a 20% improvement in skin
hydration following three sessions of hydrolift-
ing treatments. As such, hydrolifting captures
both the lifting effect (i.e., skin elasticity) and
improved hydration HA filler delivers to the skin
(Fig.  4.132). Incidentally, as skin retains more
moisture it helps improve fine wrinkles and dif-
fuse light reflection, giving the skin a bright, radi-
ant sheen. For this reason, the treatment is
colloquially referred to as the “water glow” injec-
tion. To the extent hydrolifting is effective for
improving skin elasticity, it is ideal not only for
improving low elasticity underlying preauricular
lines, photoaged skin and crépey neck wrinkles,
but also for treating dynamic lines in the malar,
nasolabial folds, cheeks, and perioral regions, not
readily treatable with BoNT-A due to the risk of
altering the  facial expression  in these areas
(Fig. 4.82). Hydrolifting is also well suited for
patients who regularly recruit the frontalis m. to
open their eyes as a compensatory mechanism
against eyelid ptosis or dermatochalasis, as the
treatment serves to soften not only static but also
severe dynamic wrinkles in the forehead which
cannot be fixed entirely with BoNT-A injections
alone. Meanwhile, horizontal creases formed
Summary 1: Use monophasic HA with
light-­to-­moderate viscoelasticity or bipha-
sic HA with fine-sized particles. The sug-
gested volume of injection is 2–4 mL per
session  for whole face. Administer HA
evenly in more than 100 points across the
deep dermis using the retrograde linear
technique. Inject using a 30-G or 33-G nee-
dle bent at a 30° angle.
Summary 2: Hydrolifting helps boost skin
elasticity and hydration and is particularly
useful for  improving the appearance of
dynamic lines in the malar, nasolabial folds,
cheeks, and perioral regions that are  not
readily treatable with boutlinum toxin
(BoNT-A) due to the risk of altering
the facial expression.
Summary 3: Epidermal sliding sign, can be
used as an indicator for determing the effi-
cacy of treatment.
Summary 4: Hydrolifting is also effective
for treating the wrinkles of the neck, elbow,
and knees.
4.20  Hydrolifting (Multiple Intradermal Injections of HA Filler)

248
above the knees in a standing position or above
the elbows when the arm is stretched straight are
also good indications for hydrolifting injections,
as they also result from decreased skin elasticity
(Fig. 4.134).
4.20.1 Pretreatment Assessment
Assess the severity and location of dynamic
wrinkles by having the patient animate the facial
expression that gives rise to the appearance of
wrinkles, and document results in the pretreat-
ment photos (Fig.  4.133). Epidermal sliding
signs, or the pleated lines appearing on the skin
when cheek is pushed with a finger, attributable
to age-related loss of skin elasticity, can be used
to determine improvements in skin elasticity
before and after the treatment (Fig. 4.132). The
choice of HA filler to be used and the desired
depth of injection is decided based on a rough
estimate of skin thickness in each treatment
case. As a general rule, the skin is thicker in men
compared with females and in sebaceous skin
compared with dry skin. Skin thickness
decreases with advancing age and in severely
photoaged skin. By facial regions, the skin is
thinnest in the periorbital region, while the neck
also displays fine skin. By comparison, skin
overlying the cheeks, malar, perioral, and fore-
head areas tends to be relatively thicker. Finally,
checks should also be made for the presence of
any static deep grooves or facial volume defla-
tion for which concurrent volumization with
HA filler may be considered for optimum
results.
Fig. 4.132  (a) Before and (b) after hydrolifting. (c) Before and (d) afer hydrolifting, epidermal sliding signs are
improved
a
b
c
d
4  Regional Particulars

249
4.20.2 Injection Technique
One of the most commonly practiced tech-
niques for reducing the appearance of dynamic
nasolabial folds is the fern technique, which
delivers HA filler in the dermis to enhance the
skin’s integrity and resilience. It involves mak-
ing multiple intradermal injections of HA filler
perpendicular to the direction of the fold from
both sides. The name “fern technique” is
derived from the rows of HA filler placed on
each side of the fold resembling the shape of
fern leaves, with the fold itself representing the
stem. The hydrolifting technique replicates the
same strategy across the entire face, as opposed
to treating a single fold or wrinkle, to address
the loss of skin elasticity  in the face.
Accordingly, where applicable, hydrolifting
injections should also be made perpendicular
to the direction of the relaxed skin tension lines
or wrinkles of the face to be treated (Table 4.19)
(Fig. 4.134).
Fig. 4.133  Dynamic expression wrinkles such as zygomatic lines, nasolabial fold and marionette line are good candi-
dates for the hydrolifting treatment
4.20  Hydrolifting (Multiple Intradermal Injections of HA Filler)

250
Regarding the choice of HA filler, injection
is to be performed using biphasic HA with fine
particles or monophasic HA with light to mod-
erate viscoelasticity, depending on the  dermal
thickness. Monophasic HA with moderate vis-
coelasticity (e.g. Belotero® Balance) or biphasic
HA with fine particles (e.g. Restylane® Vital)
may be acceptable for use in the cheeks and
malar where the skin is relatively thick. On the
other hand, monophasic HA with low viscosity
and greater spreadability (e.g. Belotero® Soft) is
more suitable for injecting areas such as the
neck and the infraorbital  areas demonstrating
reduced skin thickness. Note, however, that
while monophasic HA fillers offer the advan-
tage of increased spreadability and reduced
irregularity, their duration of effect is apparently
shorter than that of a biphasic HA filler. In the
author’s  clinical experience, Restylane® Vital
was found to last longer than Belotero®
Soft.  About 50% improvement in dynamic
wrinkles can be achieved in a single session
where cross-linked HA fillers are used. Where
results are deemed insufficient, a follow-­up
treatment can be undertaken 1 month later.
Meanwhile, the desired depth of injection is at
the deep dermis to minimize surface irregulari-
ties. When injecting manually using a 30-G
­needle, a simple test can be used to determine if
the needle is located properly in the deep dermis.
Lifting the needle upwards from under the skin, a
clear silhouette of the needle should be visible if
the needle is properly placed in the deep dermis
(Fig. 3.12). A clear silhouette of the needle is not
visible when the needle is inserted too deep into
the subcutaneous layer, while a needle inserted
too superficially in the upper dermis generates a
gray bluish hue of the needle visible through the
skin (Fig. 3.12). To prevent bumpiness in thinly
skinned areas, it is advisable to perform small
volume injections targeting the deep dermis
almost as if injecting the subcutaneous layer. The
amount of HA filler required is 0.5  mL for
the nasolabial folds or upper lip wrinkles only,
1 mL for partial treatment of the cheeks including
the nasolabial folds, 1 mL for the perioral com-
plex including the upper lip wrinkles, 1 mL for
each cheek, 1 mL for the forehead, adding up to
approximately 4 mL for the entire face. To mini-
mize bruising, it is advisable to constantly switch
treatment areas during the procedure and have an
assistant compress the area immediately after
each injection to reduce bleeding. Anesthetic
cream should preferably be applied at least
40 mins in advance to alleviate discomfort during
the  needle puncture in more than 100 points
across the tightly bounded matrix of the dermis.
The nondominant hand should be used to pull the
skin opposite to the direction of needle advance-
ment to apply tension on the skin surface.
4.20.2.1
Manual Injection Method
Manual injection of HA filler can be time-­
consuming and prone to surface irregularities
when performed with unpracticed hands. Despite
such drawbacks, manual injection ensures greater
accuracy in treating individual  wrinkles, and
therefore contributes to  maximizing the treat-
ment effect of hydrolifting. For this reason, even
where hydrolifting is primarily performed with
an injection device, manual injection can be used
synergistically to address specific wrinkles such
as dynamic nasolabial folds. The use of 30-G or
33-G needle bent at a 30° angle is advised for
performing the manual injection technique (Fig.
3.12). The entire length of needle is inserted into
the deep dermis, after which HA is delivered via
Table
4.19  Summary
of
hydrolifting
injection
technique
Item
Contents
Needle vs. Cannula
30-G, 33-G needle
27-G cannula where
bruising must be avoided
Multi-needle injector
Laser-assisted needless injector
HA filler
Monophasic HA filler with
light
viscoelasticity for thin skin
Fine biphasic HA filer or
monophasic HA filler with
moderate viscoelasticity for
thick skin
Amount of HA filler
1–4 mL per session
Depth of injection
Deep dermis
Target area
skin with low elasticity and
dynamic rhytids in the cheek,
the nasolabial folds, perioral
area, and malar area
Anesthetics
Topical anesthetics for more
than 40 min
Nondominant hand
Hold the skin to maintain skin
tension
4  Regional Particulars

251
retrograde thread technique. The needle should
preferably be directed perpendicular to the direc-
tion of the relaxed skin tension lines or wrinkles
of the face to provide better structural support to
the skin and effective treatment of dynamic wrin-
kles. Note, however, that injections parallel to the
fold may also be required to ensure maximum
treatment of the deep folds. For ease of injection,
injections should preferably be oriented from the
medial to lateral and from the inferior to  the
superior aspects of the face. Regarding the spac-
ing of injection points, HA should be delivered at
3–5 mm intervals from left to right and at 1 cm
intervals from the anterior to the posterior when
covering wide areas such as the cheek and malar.
By comparison, areas such as the upper lip
require a more thorough coverage, where HA
should be introduced at a tighter interval of
2–3 mm (Fig. 4.134). The amount of HA injected
per point is approximately 0.02 mL.
4.20.2.2
Manual Injections Using
a Cannula
In case bruising must be avoided as a matter of pri-
ority, a cannula may be used instead of a needle for
subdermal injection of HA using the same approach
as described above. Note, however, that the effects
of subdermal HA filler injection for hydrolifting are
less pronounced compared with HA injected
directly into the dermis. Injection is performed pri-
marily with a 27-G cannula, while the use of a 30-G
cannula is advised for injecting delicate fine-skinned
areas such as the infraorbital region.
4.20.3 Use of Injectors
Injection devices are capable of delivering HA
consistently at the required amount and depth
without creating surface irregularities, thus
minimizing inter-operator variability. A variety
of injectors are currently available on the mar-
ket, including Vital® injector, Neurajet®, and
DermaQueen® (Fig. 4.135). Most of the models
are available in the form of a mesogun onto
which a disposable 5–9 pin multi-needle tip is
mounted. The head of the device uses negative
pressure to create a suction between the skin
and the needle tip, allowing the needles to pen-
etrate into the skin to deliver the product
evenly  to the desired amount  and depth. The
vacuum pressure, needle depth, and injection
volume may be adjusted as appropriate accord-
ing to the indication and injection site. For thin-
Fig. 4.134  Manual method of hydrolifting technique
4.20  Hydrolifting (Multiple Intradermal Injections of HA Filler)

252
skinned areas such as the infraorbital region and
the neck, a penetration depth of 1.4  mm and
injection volume of 1μL per needle is appropri-
ate, while for thicker skinned areas, the relevant
penetration depth and injection volume should
preferably be adjusted to 1.6 mm and 2μL per
needle respectively. It generally takes 10 min to
deliver 1 mL of HA filler using a Vital Injector
featuring a 5-needle tip, based on an injection
volume of 2μL/needle, or 10μL/per shot and an
injection speed of 5–6 s per shot.
Consideration must also be given to the prod-
uct loss that may  occur from the leakage of
injected HA filler onto the skin surface.
Accordingly, the best approach is to use injectors
for delivering HA evenly across the entire face in
combination with manual injection of HA for
treating more severe dynamic wrinkles.
4.20.4 Laser-Assisted Needleless
Injector
Laser-assisted needleless injection systems such
as Mirajet® also enable hydrolifting treatments
with significantly less bruising or irregular-
ity than manual injections (Fig. 4.136). Mirajet®
is a novel transdermal drug delivery system capa-
ble of delivering drugs into the dermis without
the use of needles by leveraging the energy
released during the explosion of tissue water into
which
Erbium
YAG
laser
energy
is
absorbed.  Histologic examination in cadaveric
facial skin clearly demonstrates the presence of
HA injected into the dermis at the depth of upto
300μm by Mirajet® (Fig.  4.137) (Unpublished
data). The system is capable of propelling drugs
in a controlled amount and depth at speeds rang-
ing from 10 to 40 Hz, and thus holds a distinct
advantage over conventional injector devices in
terms of its rapid injection speed. The laser power
may be adjusted to 250–450 mW at 10 Hz, 150–
300 mW at 20 Hz, and 100–150 mW at 40 Hz,
respectively. While increasing  the laser power
can amplify the amount of drug penetration, care
must be taken to tailor the energy level to each
patient as appropriate, since an uncontrolled
firing of jet injections may inflict severe pain or
petechial bleeding (Fig. 4.138). Also, it is advis-
able to have an assistant apply proper compres-
sion on the treatment area immediately after the
procedure to minimize the appearance of injec-
tion marks. The injected medication used in the
author’s practice consists basically of HA: pla-
centa extract: PDRN (polydeoxyribonucleotide):
epi-lidocaine mixed at a ratio of 2:2:1:1 (i.e., a
three-fold dilution of HA filler combining 1 part
HA with 2 parts other ingredients). Epi-­lidocaine
containing 1:100,000 epinephrine effectively
helps to prevent severe petechia. The ratio of HA
in the formula may be adjusted according to the
patient’s age and skin elasticity (see Sect. 4.20.5).
a
b
Fig. 4.135  (a) Injector for hydrolifting, (b) multi-needle
injector tip
4  Regional Particulars

253
a
b
Fig. 4.137  Histologic examination in cadaveric facial skin clearly demonstrates the HA penetrated into the dermis at
the depth upto 300μm by Laser-Assisted Needleless Injector, Mirajet® (H&E stain, (a) X50, (b) X100)
a
b
Fig. 4.136  (a) Exterior of Mirajet® needle-free injection system, (b) transdermal drug delivery system
4.20.5 Cocktail Therapy
To further  boost the effect of hydrolifting, HA
may be synergistically combined with other
ingredients such as placenta extracts and PDRN
to  promote tissue reconstruction and regenera-
tion against cell aging while inducing elastin and
collagen remodeling via the HA placement in the
dermis. The  author’s basic formula consists of
HA: placenta extract: PDRN blended at a ratio of
2:1:1. The ratio of HA in the mixture can be
scaled upwards in patients in their fifth decade
and above displaying reduced skin elasticity and
downward-adjusted in younger patients in their
30s retaining adequate skin tightness. Some phy-
sicians opt to mix HA filler with BoNT-A to fur-
ther improve the appearance of fine lines and
pores. Indeed, multiple intradermal injection of
BoNT-A is effective not only for reducing
dynamic wrinkles but also for diminishing the
appearance of static wrinkles and pore size, which
serves to impart a glossy sheen to the skin surface
(Fig. 4.139). The improvement of fine wrinkles
and tightening of pores is attributable to the mild
lymphatic edema in the skin induced by the tran-
sient paralysis of underlying musculature from
BoNT-A injection, analogous to the swelling of
the feet during a long distance flight. The effects
of intradermal BoNT-A injections are particularly
significant in the forehead, glabella, and perior-
bital regions, and when combined with hydro lift-
ing, can give further boost to the luminescent,
“water glow” effect of hydrolifting injections in
these areas. On the other hand, combination with
BoNT-A is best avoided in the perioral and cheek
regions as inadvertent injection of BoNT-A into
4.20  Hydrolifting (Multiple Intradermal Injections of HA Filler)

254
a
b
Fig. 4.139  Improvement of pores and static wrinkles in the forehead following intradermal botulinum toxin injection
a
b
Fig. 4.138  Petechial bleeding (a). After treatment of Mirajet® needle-free injection (b) Injection marks cleared 5 days
after the procedure
the underlying mimetic muscles may cause
unwanted alterations in facial expression.
4.20.6 Wrinkles Above the Knee
Wrinkling above (i.e., superior to) the knees in a
standing position is due to the natural loss of
skin elasticity with age and is particularly com-
mon in women with reduced body weight. When
addressing these wrinkles with hydrolifting, it is
important also to concomitantly  restore the
depletion of soft tissue surrounding the knee
itself. At least 4–5 mL of HA is required per side
for volumization (replacing lost volume in the
knee), and 1–2  mL per side for hydrolifting
purposes (Fig. 4.140).
4.20.7 Complications
Irregularity (Fig. 4.141), bruising, and pain are
the most significant side effects of hydrolifting.
While best efforts should be used to minimize
such events, any surface irregularities remaining
2 weeks posttreatment should be dissolved away
4  Regional Particulars

255
with hyaluronidase injections. For severe bruis-
ing, 2–3 sessions of vascular lasers such as V
beam® can be used from the day following treat-
ment to expedite a quick recovery.
References
1. Kim HJ, Seo KK, Lee HK, Kim JS. Clinical anatomy
of face for botulinum toxin and filler injection. Berlin:
Springer; 2016. p. 93–102.
2. Mariwalla K, Germain M.  Forehead refalation. In:
Carruthers J, Carruthers A, editors. Soft tissue aug-
mentation. Philadelphia: Elsevier; 2018. p. 85–9.
3. Buso M, Howell DJ. Forehead contouring with calcium
hydroxyapatite. Dermatol Surg. 2010;36(s3):1910–3.
4. Yu Chao YY, Chhabra C, Corduff N, Fabi SG,
Hornfeldt CS, Kerscher M, Lam S, Pavicic T, Peng
PHL, Pooth R, Rzany B, Seo K, Suwanchinda A,
Tseng FW, Geister TL. Validation of a photonumeric
assessment scale for grading the slope of the Asian
forehead. Dermatol Surg. 2019;45(S1):S38–45.
5. Kim HJ, Seo KI, Lee HK, Kim JS. Clinical anatomy
of face for botulinum toxin and filler injection. Berlin:
Springer; 2016. p. 45–8.
6. Seo KK.  Botulinum toxin for Asians. Singapore:
Springer Nature Ltd.; 2017. p. 72–81.
7. Kim HJ, Seo KK, Lee HK, Kim JS. Clinical anatomy
of face for botulinum toxin and filler injection. Berlin:
Springer; 2016. p. 94–103.
8. Carruthers JDA, Carruthers JA. Volumizing the gla-
bella and forehead. Dermatol Surg. 2010;36:1905–9.
9. Beleznay K, JDA C, Humphrey S, Jones D. Avoiding
and treating blindness from fillers: a review of the
world literature. Dermatol Surg. 2015;41:1097–117.
10. Flynn TC, Carruthers JDA, Carruthers JA. Botulinum
toxin treatment of the lower eyelid improves infra-
orbital rhytides and widens the eye. Dermatol Surg.
2001;27(8):703–8.
11. Cong LY, Lee SH, Tansatit T, Hu KS, Kim
HJ. Topographic anatomy of the inferior medial pal-
pebral artery and its relevance to the pretarsal roll aug-
mentation. Plast Reconstr Surg. 2016;138(3):430e–6e.
12. Humphrey S, Fagien S. Infraorbital hollow and naso-
jugal fold. In: Carruthers J, Carruthers A, editors. Soft
tissue augmentation. Philadelphia: Elsevier; 2018.
p. 107–13.
13. Kim HJ, Seo KK, Lee HK, Kim JS. Clinical anatomy
of face for botulinum toxin and filler injection. Berlin:
Springer; 2016. p. 120–4.
14. Kim HJ, Seo KK, Lee HK, Kim JS. Clinical anatomy
of face for botulinum toxin and filler injection. Berlin:
Springer; 2016. p. 124–8.
15. Kim HJ, Seo KI, Lee HK, Kim JS. Clinical anatomy
of face for botulinum toxin and filler injection. Berlin:
Springer; 2016. p. P37–41.
Fig. 4.141  Irregularity is the main complication of
hydrolifting performed by manual technique
a
b
Fig. 4.140  (a) Before and (b) after, hydrolifting injections, the horizontal creases formed above the knees in a standing
position are improved
References

256
16. Almeida ART, Vieira Braz AV. Midfac. In: Carruthers
J, Carruthers A, editors. Soft tissue augmentation.
Philadelphia: Elsevier; 2018. p. 115–22.
17. Goodman GJ.  Facial attractiveness and the central
role of volume. In: Carruthers J, Carruthers A, edi-
tors. Soft tissue augmentation. Philadelphia: Elsevier.
p; 2018. p. 7–15.
18. Sundaram H, Huang PH, Hsu NJ, Huh CH, Wu W,
Wu Y, Cassuto D, Kerscher MJ, Seo KI, Pan-Asian
Aesthetics Toxin Consensus Group. Aesthetic appli-
cations of botulinum toxin A in Asians: an interna-
tional, multidisciplinary, pan-asian consensus. Plast
Reconstr Surg Glob Open. 2016;4(12):e872.
19. Seo KK.  Nose. In: Carruthers J, Carruthers A, edi-
tors. Soft tissue augmentation. Philadelphia: Elsevier;
2018. p. 123–33.
20. Youn SH, Seo KI.  Filler rhinoplasty evalu-
ated by anthropometric analysis. Dermatol Surg.
2016;42:1071–81.
21. Kim HJ, Seo KK, Lee HK, Kim JS. Nose. In: Clinical
anatomy of face for botulinum toxin and filler injec-
tion. Berlin: Springer; 2016. p. 139–52.
22. Casabona G. Blood aspiration test for cosmetic fill-
ers to prevent accidental intravascular injection in the
face. Dermatol Surg. 2015;41(7):841–7.
23. DeLorenzi C.  Complications of injectable fill-
ers, part 2: vascular complications. Aesthet Surg J.
2014;34(4):584–600.
24. Kim HJ, Seo KK, Lee HK, Kim JS. Hollow cheek. In:
Clinical anatomy of face for botulinum toxin and filler
injection. Berlin: Springer; 2016. p. 135–8.
25. Kim HJ, Seo KK, Lee HK, Kim JS.  Subzygoma
depression. In: Clinical anatomy of face for botuli-
num toxin and filler injection. Berlin: Springer; 2016.
p. 138–9.
26. Seo KK.  Botulinum toxin for Asians. Singapore:
Springer Nature Ltd.; 2017. p. 87–91.
27. Kim HJ, Seo KK, Lee HK, Kim JS. Nasolabial fold.
In: Clinical anatomy of face for botulinum toxin and
filler injection. Berlin: Springer; 2016. p. 128–35.
28. Jones IT, FabiS G, Carruthers J. Lip augmentation. In:
Carruthers J, Carruthers A, editors. Soft tissue aug-
mentation. Philadelphia: Elsevier; 2018. p. 141–7.
29. Kim HJ, Seo KK, Lee HK, Kim JS. Lip. In: Clinical
anatomy of face for botulinum toxin and filler injec-
tion. Berlin: Springer; 2016. p. 154–60.
30. Lee KL, Lee HJ, Youn KH, Kim HJ. Positional rela-
tionship of superior and inferior labial artery by ultra-
sonography image analysis for safe lip augmentation
procedures. Clin Anat. 2019;2:45–64.
31. Heidekrueger PI, Szpalski C, Weichman K, Juran S,
Ng R, Claussen C, Ninkovic M, Broer PN. Lip attrac-
tiveness: a cross-cultural analysis. Aesthet Surg J.
2017;37(7):828–36.
32. Kim HJ, Seo KK, Lee HK, Kim JS. Marionette line
and jowl. In: Clinical anatomy of face for botulinum
toxin and filler injection. Berlin: Springer; 2016.
p. 166–9.
33. Seo KK.  Botulinum toxin for Asians. Singapore:
Springer Nature Ltd.; 2017. p. 93–7.
34. Yu SK, Lee MH, Kim HS, Park JT, Kim
HJ.  Histomorphologic approach for the modiolus
with reference to reconstructive and aesthetic surgery.
J Craniofac Surg. 2013;24(4):1414–7.
35. Kim HJ, Seo KK, Lee HK, Kim JS. Chin. In: Clinical
anatomy of face for botulinum toxin and filler injec-
tion. Berlin: Springer; 2016. p. 160–5.
36. Koh KS, Han SH, Shin KJ, Kim HJ. Sex determina-
tion using nonmetric characteristics of the mandible
in Koreans. J Forensic Sci. 2006;51(6):1376–82.
37. Naini FB. The chin. In: Facial aesthetics, concepts
and clinical diagnosis. Oxford: Blackwell; 2011.
p. 312–34.
38. Geraghty LN.  Earlobe rejuvenation. In: Carruthers
J, Carruthers A, editors. Soft tissue augmentation.
Philadelphia: Elsevier; 2018. p. 169–73.
39. Sivek R, Emer J. Use of a blunt-tipped microcannula
for soft tissue filler injection in the treatment of lin-
ear scleroderma (en coup de sabre). Dermatol Surg.
2014;40(12):1439–41.
40. Pirrello R, Verro B, Grasso G, Ruscitti P, Cordova A,
Giacomelli R, Ciccia F, Guggino G. Hyaluronic acid
and platelet-rich plasma, a new therapeutic alternative
for scleroderma patients: a prospective open-label
study. Arthritis Res Ther. 2019;21(1):286.
41. Mashiko T, Mori H, Kato H, Doi K, Kuno S,
Kinoshita K, Kunimatsu A, Ohtomo K, Yoshimura
K.  Semipermanent volumization by an absorbable
filler: onlay injection technique to the bone. Plast
Reconstr Surg Glob Open. 2013;1(1):e4–e14.
42. Pluijmers BI, van de Lande LS, Caron CJJM, Wolvius
EB, Dunaway DJ, Padwa BL, Koudstaal MJ. Part 2:
Is the maxillary canting and its surgical correction in
patients with CFM correlated to the mandibular defor-
mity? J Craniomaxillofac Surg. 2018;46(9):1436–40.
43. de la Iglesia F, Lopez A, Mareque J, Gutierrez J,
Walter A, Puigdollers A.  Correction of mandibular
deviation and maxillary occlusal canting with man-
dibular “early” surgery and microscrews: two case
reports. Int Orthod. 2019;17(2):384–94.
44. Chalala C, Ghafari JG. Differentiation between max-
illary and malar midface position within the facial
profile. PeerJ. 2019;7:e8200.
45. Distante F.  Rejuvenation influence of a stabilized
hyaluronic acid-based gel of nonanimal origin on
facial skin aging. Dermatol Surg. 2008;34:720–6.
46. Bae GY.  Rheological properties. Filler Toxin.
2016;2(4):15–9.
47. Wilson MV, Fabi SG, Dayan SH. Neck and chest. In:
Carruthers J, Carruthers A, editors. Soft tissue aug-
mentation. Philadelphia: Elsevier; 2018. p. 157–60.
48. Landau M, Fagien S.  Science of hyaluronic acid
beyond filling: fibroblasts and their response to the
extracellular matrix. Plast Reconstr Surg. 2015;136(5
Suppl):188s–95s.
49. Wang F, Garza LA, Kang S, Varani J, Orringer JS,
Fisher GJ, Voorhees JJ. In vivo stimulation of de novo
collagen production caused by cross-linked hyal-
uronic acid dermal filler injections in photodamaged
human skin. Arch Dermatol. 2007;143(2):155–6.
50. Kerscher M, et  al. Rejuvenation influence of a
stabilized hyaluronic acid-based gel of nonani-
mal origin on facial skin aging. Dermatol Surg.
2008;34:720–6.
4  Regional Particulars

257
© Springer Nature Singapore Pte Ltd. 2021
K. K. Seo, Facial Volumization with Fillers,
Complications
5.1
Vascular Complication
5.1.1
Symptoms
Vascular compromise is the most serious compli-
cation associated with filler injection. The causes
of vascular compromise are largely two-fold, that
is, vascular embolization from inadvertent injec-
tion of product directly into the blood supply
(i.e., intravascular injection) and vascular insuf-
ficiency resulting from external compression by
the injected filler material (i.e., extravascular
compression) [1]. Extreme care must be taken to
avoid vascular occlusion due to intravascular
injection as it may bring about skin necrosis and
rare incidences of blindness in the most disas-
trous case. Vascular occlusion typically presents
with ischemic color changes such as immediate
postinjection blanching or violaceous or greyish
skin discoloration occurring 20–30  min of the
HA filler injection, for which timely and ade-
quate treatment must be administered (Fig. 5.1)
[2, 3]. If left unaddressed, multiple reticular ery-
thematous patches may develop the following
day across the nasal dorsum, glabella, and fore-
head, accompanied by epidermal sloughing and
multiple pustules in severe cases. In the extreme,
the pustules may progress to skin necrosis accom-
panied by scab formation (Fig. 4.73).
Vascular complications following the  injec-
tion of  nose fillers  are more likely to occur in
patients whose vascular circulation has already
been modified or compromised by a previous
nose surgery, or whose blood vessels have been
adhered to the scar tissue in the operated area [3,
4]. Note that vessels trapped inside scar tissue
adhesions become easy targets for penetration
during filler volumization and are substantially
more vulnerable to the risk of intravascular filler
injection. Extra care must therefore be taken
when treating a patient with a history of a previ-
ous nose surgery or removal of the nasal implant.  
5.1.2
Prevention
To minimize the risk of vascular occlusion, it is
essential for practitioners to be equipped with the
knowledge of the underlying anatomy at the
injection site, especially regarding the vascular
supply, and to strictly adhere to the relevant pre-
ventative strategies. However, even with the best
knowledge of the facial anatomy and the anatom-
ical hotspots to avoid, the risk for vascular com-
plications nonetheless persists as the vascular
supply beneath the skin surface is largely hidden
from view. Moreover, individual variations exist
in vascular distribution patterns. As a key preven-
tion strategy against vascular embolization,
therefore, it is highly recommended that a can-
nula be used instead of a needle for facial volu-
mization with fillers. That said, precaution is still
required even with the use of cannulas as small-­
diameter cannulas remain capable of piercing
through a vessel. To optimize safety during filler
administration, the use of cannulas sized 25 or
5

258
a
b
c
d
e
f
g
h
5  Complications

259
larger, gentle maneuvering of the instrument, and
slow, low pressure injection using the retrograde
linear technique are advised wherever feasible to
mitigate the risk of intravascular filler injection.
Where the use of a needle is inevitable, it is
essential to make sure the injection is made into
a relatively avascular plane. For example, when
performing reshaping of the nose with a needle,
injection should preferably be limited to the nasal
radix where deep injection directly onto the peri-
osteum is advised as the vasculature at the upper
nasal dorsum runs superficially close to the skin
surface (see Sect. 4.9.13). In the case of forehead
augmentation, the supraperiosteal layer is a safe
avascular zone for the same reason. In addition,
aspiration prior to each injection is required when
injecting with a needle to ensure the needle tip is
not placed in a blood vessel. Note, however, that
the results of blood aspiration tests are not neces-
sarily failproof as the test may produce false neg-
atives, especially where the injection was
performed using gel-type HA fillers or small
diameter needles (see Sect. 4.9.13).
Practitioners should pay close attention to any
ischemic color changes occurring during or
immediately after filler injection that alert them
to a possible vascular occlusion, in which case
timely and adequate intervention including injec-
tion of hyaluronidase in and around the lesion is
required. Of the five cases of vascular occlusions
from filler rhinoplasty encountered by the author,
the event went unnoticed during the treatment in
three cases, and it was not until the next day that
mottled erythematic patches began appearing on
the patient’s face, which took approximately
1  month to fully disappear without severe
sequelae. Since then, it has been the author’s pol-
icy to have the patient remaining in the office for
30 mins after nose filler injections to ensure early
detection of any ischemic skin changes. Patients
are also advised to immediately revert back to the
clinic upon noticing any violaceous changes in
the skin occurring within 1–2 h of their depar-
ture. Finally, one cannot overstate the value of
using reversible HA fillers to guard against unex-
pected events of vascular occlusion occurring
even with the best preventative procedures in
place. Specifically, HA should be the preferred
choice for treating the high-risk areas for vascu-
lar occlusion including the nose, glabella, nasola-
bial fold, and forehead (Table 5.1).
5.1.3
Treatment
In the event of vascular embolization due to intra-
vascular filler injection or vascular insufficiency
from external compression of weak vessels by
the surrounding HA filler, the injected HA must
be dissolved away immediately with hyaluroni-
dase. While it is next to impossible to inject hyal-
uronidase into the precise location in the vessel
where the occlusion is present, it has been postu-
lated by De Lorenzi et  al. that hyaluronidase
infused in sufficient amounts generally around
the area where the ischemic symptoms are pres-
ent may effectively traverse and diffuse across
the arterial wall to reach the hyaluronic acid held
Fig. 5.1  Case of vascular complication after nose filler
which was immediately and successfully treated with
hyaluronidase injection. (a) Day 1. a 35-year-old woman
showed blanching, violaceous or greyish skin discolor-
ation on the dorsum of nose 20–30 minutes after nasal
dorsum augmentation using HA filler and a 30G needle.
Her nose was immediately injected with hyaluronidase.
(b) Day 2. Multiple reticular erythematous patches
developed across the nasal dorsum, glabella and fore-
head. Bruising due to injection of hyaluronidase devel-
oped in the right lower eyelid and sclera. (c) Day 4.
Multiple tiny pustules developed in the leseion. (d) Day
7. Epidermal sloughing and crust developed in the
leseion. (e) Day 10. Yellowish crust and erosion still
remained. (f) 1 Month. The wound healed with surface
irregularities and hyperpigmentation on the erythema-
tous base. (g) 3 Months. Mild erythematous patches with
mild depressed scars still remained. (h) 7 Months. The
lesions completely resolved without any seqaule. (Photo:
Courtesy of Dr. Kim Sang-Yeon)
5.1  Vascular Complication

260
in the blood vessel [4]. Hence, in order to resolve
occlusions of hyaluronic acid fillers it is advised
to infiltrate hyaluronidase subcutaneously in
copious amounts (3–6 mL) at a high concentra-
tion (750 U/mL) around the tissue where isch-
emic symptoms such as blanching, greyish
decolorization, or mottled erythema are sus-
pected (see Sect. 5.4).
The effective timing of hyaluronidase injection
for such vascular events is within 24 hours of HA
filler injection. This is also backed up by the find-
ings of an animal study in which vascular occlu-
sion was induced in rabbit ears using HA filler, to
which hyaluronidase was subsequently injected at
different intervals [5]. While hyaluronidase
injected within 4 h was beneficial in clearing the
occlusion, it had little effect after 24 h. Accordingly,
patients demonstrating even the slightest signs of
ischemia should be observed for 20–30 min in the
office for any further development of symptoms.
Progression of symptoms calls for immediate
injection of hyaluronidase. Regardless, even after
the 24-hour window, there may still be some value
to giving hyaluronidase injections as a placebo for
the patient and as protection for the practitioner
from the legal consequences of denying such
­intervention. Apart from the  administration of
­hyaluronidase, sublingual nitroglycerin tablets
administered twice at 30 min intervals (i.e., two
tablets given 30 min apart) together with oral aspi-
rin and sildenafil (or tadaifil) is necessary to facili-
tate systemic blood circulation. Intramuscular
injection of steroids such as dexamethasone is also
recommended for reducing inflammatory reaction
while antibiotic administration is advised to pre-
vent secondary infection.
In case the patient presents to the clinic after
the golden hour of treatment (i.e., the first 24 h)
has passed, presenting with severe symptoms
including multiple pustules, skin necrosis, and
crust formation, all of the aforementioned treat-
ment modalities, including hyaluronidase injec-
tion, should be applied in tandem, except for oral
nitroglycerin which should be given only during
the acute phase. The use of hyperbaric oxygen
treatment (HBO) is also advisable, where appli-
cable, for treating peripheral ischemic symptoms
[2] (Table  5.1). Concurrent injection of PRP
(platelet-rich plasma), stem cell extracts, or pla-
centa extract once daily during the first week,
twice weekly during the first month, and once
weekly thereafter for 3 months can also be help-
ful combined with EGF (epidermal growth fac-
tor) spray or ointment (Fig. 4.73). Bleaching
treatment such as laser toning using Nd:YAG
laser is recommended combined with bleaching
topical agents such as hydroquinone in the case of
postinflammatory hyperpigmentation. Vascular
lasers such as V-beam would be helpful for the
treatment
of
erythematous
lesions
after
the crust has been removed, with fractional laser
for the scar tissue.
Table 5.1  Prevention and management of vascular complication from filler injection
Prevention
Management
1. Thorough knowledge of the facial anatomy,
especially facial vessels
2. Routine use of HA filler
3. Routine use of cannulas 25-gauge or larger
4. Routine aspiration prior to injection when needle
is used
5. Injection into the avascular plane such as deep
supraperiosteal layer of forehead and nasal radix
when needle is used
6. Retrograde injection technique
7. Slower injection speed with lower pressure
8. Smooth progression of the cannula
9. Extra precaution when treating patients with a
previous record of surgical procedure in the area
1. Hyaluronidase injection subcutaneously in large amounts
(3–6 mL) at a high concentration (750 U/mL) into the lesion
and the adjacent area for HA fillers. Immediate retrobulbar
administration of hyaluronidase in large volumes (>4500–
6000 U) and high concentrations (1500 U/mL) can help
counteract the risk of permanent blindness.
2. Application of topical nitroglycerine
3. Sublingual nitroglycerin
4. PO sildenafil or tadalafil
5. PO aspirin (100 mg)
6. PO steroid
7. PO antibiotics
8. Warm massage
9. Hyperbaric oxygen treatment if available.
5  Complications

261
5.1.4
Cause and Treatment
of Blindness Following HA
Filler Injection
Occlusion of facial arteries due to intra-arterial
injection of HA filler can lead to the serious com-
plication of skin necrosis. Inadvertent entry of
the product into branches of the ophthalmic a.
including the supratrochlear a., supraorbital a.,
and dorsal nasal a., however, can lead to the
instantaneous and catastrophic consequence of
visual loss. Blindness secondary to filler injec-
tion is caused by the backflow of the filler
embolus from the above arterial branches into the
ophthalmic a., from which the material is pushed
down by the arterial pressure into the central reti-
nal a. and posterior ciliary a. which supply the
retina, resulting in retinal embolism [6, 7]
(Fig. 5.2). According to the literature review by
Beleznay et al. regarding cases of blindness fol-
lowing filler injection, the risk of blindness from
filler was the highest at the glabella (38.8%), fol-
lowed by the nasal region (25.5%), nasolabial
folds (13.3%), and forehead (12.2%) [6]. By
filler type, autologous fat (47.9%) was the most
common cause followed by hyaluronic acid
(23.5%) [6]. In 23.5% of the cases, blindness was
also accompanied by incidence of central ner-
vous system complications caused by the intro-
duction of the filler material into the cerebral
circulation.
As noted, various facial regions commonly
injected with fillers can serve as unintended path-
ways to vision loss if not become targets of local-
ized vascular occlusion. For example, HA filler
placed in the glabella and forehead and acciden-
tally entering the supratrochlear a. or supraorbital
a. may flow retrograde into the ophthalmic a. and
obstruct blood supply to the retina. Likewise, HA
filler injected in the nose or nasolabial folds may
also be transported up to the ophthalmic a. via the
rich anastomoses present between the dorsal
nasal a. (as a direct branch of the ophthalmic a.)
and the various branches of the facial a. such as
the angular a. and lateral nasal a.
Blindness has been found to occur even from
HA filler injection in the lips and the chin. The
mechanism may best be explained by the reverse
flow of the HA filler emboli from either the infe-
rior and/or superior labial a. back into the facial
a. after which the material is sent traveling up the
branches of the facial a. and into their intercon-
nections with the dorsal nasal a. which joins into
the ophthalmic a. Meanwhile, HA filler inadver-
tently injected into the inferior medial palpebral
artery (IMPA) running parallel to the lower eye-
lash during pretarsal roll augmentation can also
cause vision loss since the IMPA constitutes a
branch of the ophthalmic a [1]. Rare cases of
blindness have also been reported following tem-
ple enhancement with HA filler [6]. Presumably,
this is caused by the retrograde flow of HA filler
from the deep temporal a. into the maxillary a.
and its subsequent delivery into the infraorbital
branch of the maxillary a. which communicates
with the dorsal nasal and inferior palpebral
branches of the ophthalmic a.
Arterial occlusion of the retina presents with
immediate impairment of vision and acute pain
in the eyes. As of yet, no treatment has proven to
be entirely successful in restoring patients from
filler–related blindness except for  retrobulbar
hyaluronidase injection [8–11]. According to
Zhu et  al. [9], even retrobulbar hyaluronidase
injection has been shown to lack efficacy as a res-
cue treatment for patients with HA filler-induced
vision loss, despite being the most novel treat-
ment protocol  so far. However, one possible
counterargument might be that such findings
stem from the untimely implementation of the
retrobulbar technique, that is, after the critical
golden hour for the treatment had elapsed.
Indeed, in an animal study involving monkeys,
the critical window of opportunity for restoring
retinal function was found to be within 97 min of
clamping of the central retinal a., with irrevers-
ible blindness occurring after 4 h of the clamp
down and blockage of the blood supply.
On the contrary, Lee et al. [11] have found in
their recent animal study that retrobulbar hyal-
uronidase injection administered in high doses
and concentrations within minimum time was
effective in dissolving the HA filler emboli from
the central retinal a. in rabbit eyes. Specifically,
three out of four rabbit eyes with an occluded
central retinal a. achieved immediate arterial
5.1  Vascular Complication

262
recanalization upon retrobulbar injection of
3000 U (2 mL) of hyaluronidase within 10 min of
the onset of the arterial occlusion.
From this, it may be surmised that hyaluronidase
infiltrated in high doses and high concentrations
may diffuse effectively across the walls of the oph-
thalmic/central retinal arteries to dissolve the HA
filler held in the blood vessels. Such findings sug-
gest that, if vision loss is suspected, immediate
retrobulbar administration of hyaluronidase in
large volumes (>4500–6000 U) and high concen-
Fig. 5.2  Blindness secondary to filler injection is caused by
the backflow of the filler embolus from the supratrochlear a.,
supraorbital a. and dorsal nasal a. into the ophthalmic a.,
from which the material is pushed down by the arterial pres-
sure into the central retinal a. and posterior ciliary a. which
supply the retina, resulting in retinal embolism
5  Complications

263
trations (1500 U/mL) can help counteract the risk
of permanent blindness. To prevent injury to the
eyeball, a 27G 3 cm cannula or blunt tip needle
(Atkinson needle) should be used to perform the
retrobulbar injection of hyaluronidase, with the
cannula inserted through the inferior eyelid and
advanced to the back of the eye parallel to the
orbital floor. The cannula entry point is created
where a vertical line drawn from the lateral can-
thus meets the bony orbital rim (Fig. 5.3). To avoid
a
b
Fig. 5.3  Technique for retrobulbar injection of hyaluron-
idase. (a) The cannula entry point is created where a verti-
cal line drawn from the lateral canthus meets the bony
orbital rim. (b) To avoid injury to the eyeball, the cannula
should be inserted in an inferomedial direction 2 cm into
the orbital floor, after which it should be redirected supe-
riorly and advanced for an additional 1 cm before hyal-
uronidase is injected
5.1  Vascular Complication

264
injury to the eyeball, the cannula should be inserted
in an inferomedial direction 2 cm into the orbital
floor, after which it should be redirected superiorly
and advanced for an additional 1 cm before hyal-
uronidase is injected [12]. However, it must be
noted that this technique carries the risk of retro-
bulbar hemorrhage in rare cases. Another option
for placement of hyaluronidase into the extraocu-
lar  muscle cone is performing a Sub-­Tenon’s
block. This technique requires first making a small
opening in the conjuctiva and then another opeing
in the Tenon’s layer using Wescott scissors and
toothed forceps. The Wescott scissors are then
used to bluntly dissect into the retrobulbar space,
or the sub-Tenon’s plane. Next hyaluronidase is
delivered via a blunt cannula into the muscle cone
[13]. Retrobulbar injection of hyaluronidase must
be administered immediately upon presentation of
symptoms as the critical window of treatment is
7 mins and irreversible blindness begins occurring
after 4 h. In case the first injection yields no results,
reinjection of hyaluronidase may be attempted 10
mins. later.
5.2
Inflammation from Delayed-­
Type Hypersensitivity to 
HA Filler
Hyaluronic acid (HA) is well-suited for use as
injectable filler as it consists of the same polysac-
charides that constitute our body and therefore
has an  excellent safety and tolerability profile
with minimum immunogenicity compared with
protein-based  injectables. For this reason, HA
represents the world’s most widely used type of
injectable filler for facial volumization. However,
with the surge in HA filler procedures performed,
there has been a corresponding increase, though
still rare, in reports of immune-related adverse
events such as delayed-type hypersensitivity
associated with the use of H A fillers.
Currently, little is reported in the literature
concerning
delayed-type
hypersensitivity
­reactions which manifest in the form of acute
inflammation, symptoms of which include
­swelling, tenderness, or local heating distinct
from granuloma  formation. Further, due to its
apparent overlap in symptoms with inflammation
from infection, delayed-type hypersensitivity is
often incorrectly diagnosed and treated as an
infectious reaction. However, it is important for
the injecting physician to be able to identify and
distinguish inflammation from  delayed-type
hypersensitivity from an infection as it can be
treated effectively with the use of steroid alone
without implicating the use of antibiotics.
5.2.1
Cause of Delayed-Type
Hypersensitivity Following HA
Injection
According to the Gell and Coombs classification,
delayed-type hypersensitivity is categorized as a
type IV hypersensitivity reaction which is defined
as
an
antibody-independent
cell-mediated
immune memory response [14]. It is initiated
when a memory T cell previously activated by an
antigen releases various cytokines upon repeat
exposure to the same antigen, triggering a pleth-
ora of late-onset reactions. In contrast to the other
antibody-dependent hypersensitivity types (I–III)
in which immune reactions kick off within min-
utes or hours upon presentation to the antigen,
type IV hypersensitivity reactions characteristi-
cally start after a delay of 48–72 h. Exactly which
specific component of the HA filler causes this
delayed-type hypersensitivity has not yet been
clearly identified, and may conceivably vary
from case to case.
According to one school of thought, hyal-
uronic acid itself, as the principal ingredient of
HA fillers, may be capable of triggering an
immune response [3, 15, 16]. This theory is sup-
ported, in particular, by a prior study suggesting
the possibility of low-molecular-weight HA to
induce the presentation of inflammatory cyto-
kines such as IL (interleukin)-12 or TNF (tumor
necrosis factor)-alpha, which serve to exacerbate
the inflammation. Indeed, HA skin testing occa-
sionally yields positive responses, while HA anti-
bodies are sometimes detected in the patient’s
blood. [16] However, perhaps a more plausible
explanation involves the presence of trace impu-
rities not entirely removed during the HA filler
manufacturing process [17]. These include resid-
ual bacterial protein, DNA or the cell organelle,
5  Complications

265
bacterial endotoxin, or any lingering amounts of
the cross-linking agents (BDDE) in the final
product. Most of the commercially available HA
fillers are manufactured through the process of
extraction and purification of HA from bacteria,
that is, streptococcus, and may contain trace
quantities of bacterial impurities such as protein,
DNA, cell organelle, or endotoxin. HA is classi-
fied as food grade, cosmetic grade, or medical
grade which is further subclassified as those
licensed for use as ophthalmic agents or as inject-
able preparations, depending on the stringency of
the purification performed [16]. In each case,
market authorization is granted upon the product
satisfying the minimum regulatory standard,
which is also the case for the licensing of medical-­
grade HA. [17] HA purification is a costly pro-
cess requiring a hefty investment of time,
resources, and CAPEX on the part of the
­manufacturer. The sheer cost burden, combined
with the minuscule incidence of delayed-type
hypersensitivity reactions associated with the
product, may disincentivize manufacturers from
committing additional resources solely for the
purpose of minimizing bacterial impurities. This
naturally explains the varying incidence of
inflammation from delayed hypersensitivity in
different HA filler products. Meanwhile, the
cross-linking agent BDDE may also play a role in
causing inflammation from delayed-type hyper-
sensitivity. In this respect, it bears noting that
delayed-type hypersensitivity has also been
found to occur in the recently launched longer
lasting HA products which incorporate a higher
degree of cross-linking or higher BDDE content
to boost longevity.
While the exact cause of delayed type hyper-
sensitivity to HA remains largely open to debate,
in the author’s view, residual bacterial impurities
not fully removed during purification appear to be
the primary culprit. In my practice, I have found
cases where a patient with a history of delayed
inflammation to one HA filler brand was treated
uneventfully with a different brand of HA filler. I
have also anecdotally observed cases where a
patient who had been injected with two different
types of HA filler respectively in two different
facial areas developed hypersensitivity reactions
subsequently in only the area injected with a par-
ticular HA filler. On top of this, there has been
cases, though rare, of continued recurrence of
inflammatory reactions even after the full dissolu-
tion of the underlying HA filler several months
prior. Together, these cases point to the likelihood
of residual bacterial impurities being the more
likely root cause of delayed type hypersensitivity
than the HA itself.
5.2.2
Symptoms
5.2.2.1 Case
A 26-year-old female patient presented com-
plaining of swelling and induration in her left
medial malar, which had occurred since the pre-
vious day (Fig. 5.4a). She had previously received
2 cc of HA injection in each medial malar 8 weeks
prior. There had been no subsequent history of
trauma or the use of injectables or surgery in the
relevant site, except for the patient returning from
a trip 1 week prior, after which she reportedly
experienced some degree of fatigue. Upon physi-
cal examination, the presence of erythema-
tous  swelling, induration, and mid tenderness
were noted in the area. An intramuscular injec-
tion of 5 mg of Dexamethasone was administered
together with oral prednisolone 20 mg/day for
2  days. Rapid recovery was achieved with no
relapse thereafter.
Illustrated above is a classic case of an inflam-
matory reaction from delayed-type hypersensi-
tivity following HA injection. Clinical symptoms
generally include swelling, induration, erythema,
localized heat, and pain or tenderness in the
treated area, though in mild cases, only swelling
and induration may be present. Occasionally,
eczema seborrheicum, lupus erythematosus or
other forms of dermatitis of the face unrelated to
HA injection may be confused as inflammation
from delayed-type hypersensitivity since the for-
mer symptomatically displays erythema and
localized heat as well. However, delayed-type
hypersensitivity cannot be diagnosed simply
based on the presence of erythema and localized
warmth alone. Instead, swelling and induration
must be identified as they are present even in
mild cases of delayed-type hypersensitivity
hence serving as more reliable indicators.
5.2  Inflammation from Delayed-Type Hypersensitivity to HA Filler

266
Concerning the timing of onset, a wide variation
exists among  published reports, ranging  from
1 month postinjection to as long as 3 years postin-
jection [17]. Contrary to acute inflammatory
reactions due to infection which typically occur
within 2–3 days of HA filler injection, inflamma-
tion from delayed-type hypersensitivity starts
2–4 weeks postprocedure at the earliest and may
occur even as late as 16 months postprocedure
based on the author’s clinical experience.
Incidence of inflammation from delayed-
type hypersensitivity varies by product. Based
on the literature review, the prevalence of
immune-­mediated reactions following HA
injections was found to vary, from 0.8% in one
study, of which 0.3% represented delayed
hypersensitivity to 0.04–0.7% in a European
study [16]. However, these numbers do not per-
tain squarely to the prevalence of delayed
inflammation from delayed-type hypersensitiv-
ity to HA filler as they also cover cases of
delayed
granuloma
due
to
delayed-type
hypersensitivity.
The incidence of inflammation from delayed-­
type hypersensitivity in the HA products used in
the author’s own practice at Modelo Clinic is less
than 0.3%. On a related note, a local HA product
is known to have been voluntarily withdrawn
from the market shortly following its release due
to the high incidence (>10%) of delayed-type
hypersensitivity inflammatory  reactions. While
less than 0.3% may seem negligible numbers-­
wise, understanding that it can be deeply distress-
ing for the individual patient going through the
symptoms, it may be worthwhile to alert them to
this risk during consultation as the patient may
assume the reaction to be the result of faulty
filler placement. Personally, my preferred prod-
uct to use in patients visiting from abroad or out-
side of Seoul is Belotero® (Merz), given its
minimal incidence of delayed-type hypersensi-
tivity reactions. That being said, I have observed
cases of inflammatory reactions  from  delayed-­
type hypersensitivity even with the use of
Belotero® Volume, while Restylane® SubQ in the
same patient had proven to be uneventful. In
other cases, the patient responded unfavorably to
both products.
While the exact etiology of inflammation from
delayed hypersensitivity to HA remains unclear,
more than half of the patients who eventually
developed hypersensitivity reactions in my prac-
tice reported of having undergone a certain
stressful event such as a flu, long-distance trip
a
b
Fig. 5.4  Cases of inflammation from a delayed-type
hypersensitivity reaction to HA filler. (a) The tender ery-
thematous swelling with induration developed in the right
cheek 8 weeks post-injection in a 26-year-old female
patient injected with Restylane® SubQ to address hollow-
ness in the bilateral infraorbital and anterior medial malar
regions. (b) A 36-year-old female patient injected with
Neuramis® Volume for the chin augmentation developed
tender erythematous swelling in the chin 16 month
post-injection
5  Complications

267
abroad, or working late hours prior to the out-
break, which may possibly have primed their
body’s immune response. Indeed, according to
one study, approximately 40% of delayed-onset
granuloma following Juvederm® Voluma injec-
tion was found to have been accompanied by a
trigger, such as a cold or a dental procedure,
which may have disrupted the patients’ immune
system. While together these cases suggest a
higher
likelihood
of
inflammatory
reac-
tion from delayed-type hypersensitivity during a
state of reduced immunity, they fall short of
establishing a clear causation given that delayed-­
type hypersensitivity also occurred in the absence
of a trigger.
In 2/3 of cases based on the author’s experi-
ence, inflammation from delayed hypersensitiv-
ity is a one-off event with no recurrence of
symptoms thereafter. However, in the remaining
1/3 of the affected patients, a relapse has been
found to occur 1–4 weeks after the initial resolu-
tion of symptoms. In extremely rare cases, how-
ever, the patient may experience similar
symptoms even after the HA filler had been fully
dissolved with hyaluronidase.
5.2.3
Differential Diagnosis
An important distinction should be drawn
between inflammation arising from delayed-type
hypersensitivity and inflammation with an infec-
tious origin since a striking similarity exists in
their symptoms, namely tenderness, erythema-
tous swelling, induration, and local heating.
On diagnostic tests, inflammation from
delayed-type hypersensitivity can show elevated
levels of nonspecific acute phase proteins such as
fibrinogen or CRP, which also happen to appear
in testing for infection-induced acute inflamma-
tion. While ideally, culture identification should
provide conclusive evidence of any bacterial
infection, it often produces negative results due
to its failure to isolate the causative bacteria [18].
Infection from HA filler injection is caused pri-
marily by the introduction of the staphylococcus
residing on the skin surface into the tissue, where
it forms a biofilm around the injected filler. The
staphylococcus then tends to maintain a low level
of virulence to evade host immune response or
the effect of antibiotics.
HA filler-related infection may also be caused
by the activity of a nontuberculous mycobacte-
rium. Based on the speed of growth, mycobacte-
ria consist of the rapidly growing nontuberculous
mycobacterium and the slow-growing nontuber-
culous mycobacterium. Of these, the rapid grow-
ers, specifically, M. fortuitum and M. abscessus
are mainly responsible for the lesions caused dur-
ing an invasive procedure. As a matter of fact,
there is one case of M. abscessus infection fol-
lowing HA injection reported overseas, where the
procedure had been performed by a nonlicensed
injector [19]. Lesions of nontuberculous myco-
bacterial infection manifest as nodules, patches,
or abscess.
Given the remarkable similarity in symptoms
between inflammation arising from delayed-type
hypersensitivity and infection-induced inflam-
mation, both of which manifest as acute inflam-
matory reactions, the key distinguishing factor is
the timing of their onset. An inflammatory reac-
tion occurring within 2–3 days of treatment sug-
gests infection, while inflammation developing at
least 2–4  weeks after the HA injection most
likely indicates delayed-type hypersensitivity. In
the author’s clinical experience, the longest dura-
tion from HA injection until the outbreak of
inflammatory reactions around the site of filler
injection was 16  months. Also, inflammation
occurring sporadically in multiple sites is more
likely to be a delayed-type hypersensitivity reac-
tion. More specifically, inflammation spreading
simultaneously or consecutively in multiple areas
in and around the injection site indicates a
delayed-type hypersensitivity reaction whereas
infections tend to be confined mainly to one
localized area. Of course, this does not represent
the absolute criteria as delayed-type hypersensi-
tivity reactions can also start initially from one
localized area before developing in other facial
regions with time. Infection may also involve the
formation of an abscess, in which case a throb-
bing fluctuation may be felt in the infected area.
The final point of differentiation is whether the
symptoms respond to standalone treatments
5.2  Inflammation from Delayed-Type Hypersensitivity to HA Filler

268
using steroid without the combined use of antibi-
otics, since infections do not respond to such
monotherapy without antibiotics.
5.2.4
Treatment
Steroids alone provide effective treatment for
inflammation from  delayed-type hypersensitiv-
ity. A single intramuscular injection of 5  mg
dexamethasone where practicable combined with
oral administration of prednisolone 10 mg twice
daily for 3–5 days results in complete resolution
[16, 19]. The combined use of analgesics and
anti-inflammatory drugs may be considered to
relieve any accompanying pain. Significantly,
antibiotics are not necessary for treating inflam-
mations from delayed-type hypersensitivity as
symptoms do not arise from an infection. While I
had also previously relied on the combined use of
antibiotics for treating delayed-type hypersensi-
tivity due to fears of possible infection, since
some 6 years ago I converted to the use of ­steroids
alone, based on which 100% recovery is achieved.
As previously noted, roughly 2/3 of hypersensi-
tivity cases are cleared as a single isolated epi-
sode with no recurrent attacks. However, a
relapse may occur in the remaining 1/3 of the
cases 1–4 weeks following a successful resolu-
tion, in which case it is preferable to dissolve the
problematic HA filler with hyaluronidase.
Reversal of HA filler may be considered even
upon initial presentation of the inflammation
where symptoms are particularly severe or where
a speedier 1-day recovery is desired. While no
published guidelines are available regarding the
appropriate dose of hyaluronidase, in my clinical
experience, 30  U of hyaluronidase per each
0.1 mL of HA filler provides quick resolution as
the HA filler softens within hours and completely
dissolves away within a day.
5.2.5
Summary
To recap, HA represents the world’s most widely
used injectable filler for facial volumization
owing to its biocompatibility and minimal immu-
nogenicity. While rare, however, immune
responses may occur following HA filler injec-
tions, and in ths respect, understanding the char-
acteristics
of
delayed-type
hypersensitivity
reactions is critically important. Inflammations
from delayed-type hypersensitivity share many
clinical symptoms with infection but must be dis-
tinguished as the pertinent treatment is different.
In contrast to infection, delayed-type hyper-
sensitivity characteristically develops with a time
lag of at least 2–4 weeks if not several months
from the HA injection, and responds favorably to
steroid monotherapy without the combined use
of antibiotics. While the exact cause of inflamma-
tion from delayed-type hypersensitivity remains
unclear, I theorize that it is most likely caused by
the delayed release of trace bacterial impurities
or BDDE not properly removed during the purifi-
cation of HA filler.
In my experience, I have anecdotally found
that a patient treated using two different HA fill-
ers in two different facial areas may present
inflammatory reactions from delayed-type hyper-
sensitivity only in the site injected with a particu-
lar HA product.
Also, I had patients who had previously devel-
oped an inflammatory reaction  from  delayed-­
type hypersensitivity to one brand of HA filler
but were treated without event when switched on
to a different HA fillerbrand. Finally, while rare,
there have been cases where inflammatory reac-
tions were found to reoccur months after the
complete dissolution of the underlying HA filler.
While inflammation from delayed-type hyper-
sensitivity arises primarily due to product/patient
factors, patients may mistakenly assume it to be a
technique issue on the part of the pratictitioner,
and should therefore be alerted to such risks
before treatment. In case a delayed-type hyper-
sensitivity reaction occurs, steroids alone provide
excellent treatment. However, in approximately
1/3 of the cases, a relapse may occur 1–4 weeks
following successful treatment, in which case it is
best to have the HA filler dissolved with hyal-
uronidase. The dissolved HA filler can be replaced
with a different HA product if the patient so
desires. Note, however, that hypersensitivity reac-
tions may recur even after switching to a different
HA filler. In this case, the use of HA filler should
be contraindicated in the patient as recurrence
5  Complications

269
suggests the patient has an inherent hypersensitiv-
ity to either the HA itself and/or the crosslinker.
5.3
Posttreatment Contour
Irregularity
Contour irregularity represents the most common
complication associated with the use of volumiz-
ing HA fillers. Depending on the underlying
cause, they range from transient lumpiness from
immediate postinjection swelling which resolves
spontaneously within a week, or an uneven con-
tour caused by inadequate placement technique
or insufficient injection volume, to those occur-
ring weeks or months following an otherwise
successful procedure due to variations in indi-
vidual physiological factors. Fortunately, such
undesirable outcomes can readily be reversed by
the administration of hyaluronidase to the extent
HA filler had been used for the treatment.
Contour irregularity following a HA filler pro-
cedure falls largely into those stemming from the
inadequate placement of HA filler and those
developing gradually long after the initial HA
filler procedure. Inadequate placement, in turn, is
attributable to the practitioner’s lack of skill or
insufficient injection volume. Alternatively, it can
also occur when only one localized area of the
face is treated without regard to the balance and
harmony with the rest of the face.
Meanwhile, there are cases where the irregu-
larities may not be apparent in the first instance
but appear over time due to the following factors:
subsequent aggregation of HA filler caused by
surrounding muscle contraction, gradual swell-
ing of HA filler due to its hydrophilicity, or varia-
tions in the longevity of HA fillers at different
facial regions [20]. This chapter elucidates the
various underlying causes of posttreatment con-
tour irregularities and provides the relevant strat-
egies for their correction and management.
5.3.1
Inadequate Placement
5.3.1.1 Inadequate Positioning
Overfilling the lower pretarsal area during a pret-
arsal roll augmentation may cause the injected
volume to spill over into the adjacent infraorbital
fat region exacerbating the puffiness of any
undereye bags. Likewise, overcorrection of the
canine fossa during a nasolabial fold correction
may cause the excess volume to migrate upward,
creating a doughy, pillowy appearance in the
nasolabial fat pads (Fig. 5.5).
5.3.1.2 Inadequate Technique
While no facial region is immune to the risk of
contour irregularity where suboptimal techniques
have been employed, certain areas are particu-
larly at risk, namely, the periorbital area where
the skin is exceptionally thin and the nasal and
frontal regions where only limited space is avail-
able for HA filler placement.
Irregularity is a common complication of
forehead augmentation. Unevenness in forehead
contour may occur immediately after HA injec-
tion or develop with a time lag of 3–6 months
posttreatment due to the contraction of the sur-
rounding muscles. The former is most likely the
result of a suboptimal placement technique, that
is, failure on the part of the practitioner to dis-
tribute filler evenly across the forehead. Such
failures are more apt to occur with the use of a
needle as opposed to a cannula. When I was first
in practice, it was common practice to use a
1.25 cm sharp needle to perform forehead aug-
mentation as cannulas had yet to be introduced
Fig. 5.5  A case of inadequate placement. Overcorrection
of the canine fossa during a nasolabial fold correction
may cause the excess volume to migrate upward, creating
a doughy, pillowy appearance in the nasolabial fat pads
5.3  Posttreatment Contour Irregularity

270
at the time. The exercise was not only time-con-
suming but was also fraught with the risk of
irregularities. In contrast, a cannula is ideal for
creating a smooth, even forehead contour as its
longer length allows better reach into multiple
different areas across the forehead into  which
volume can be distributed evenly from a given
entry point.
Meanwhile, the periorbital area, with its
reduced dermal thickness, is also vulnerable to
contour irregularities. For example, overcorrec-
tion of the tear trough can often lead to the devel-
opment of the Tyndall effect or the appearance of
disfiguring lumps. Unevenness can occur particu-
larly where the HA filler is added in the tear
trough only without considering the lack of vol-
ume in the malar region below to support it
(Fig. 5.6). Treatment of sunken eyes with filler is
also prone to developing unevenness in contour,
which may become more noticeable when the
eyes are closed (Fig. 4.23). Therefore, a moderate
undercorrection is advised when treating the
sunken eyes, preferably aiming for only 60–70%
correction with the eyes open. Pretarsal roll aug-
mentation is also susceptible to lumpiness where
the injection lacks smooth consistency, or too
little volume is injected into loose saggy lower
pretarsal skin. Also, in patients with a history of
lower eyelid blepharoplasty or trichiasis surgery,
postsurgical scar tissue adhesions in the area tend
to prevent adequate filler placement along the
lash line and are likely to cause lumpiness even
when the filler is placed inferior to the lash line
(Fig. 4.28).
5.3.1.3 Insufficient Injection Volume
Occasionally, treatment may appear perfect in the
first instance owing to the additional volume cre-
ated by postinjection edema, only to reveal subtle
irregularities 1–2 weeks later as the swelling sub-
sides. It is necessary to inform the patient of this
possibility in advance since he/she might other-
wise misunderstand it as a technique issue. The
patient should be further advised that the purpose
of scheduling a follow-up visit 1–2 weeks post-
treatment is so that any such opportunities for
adjustments may be identified.
It also bears noting that the primary purpose
of volumizing fillers is to literally fill out areas of
volume deficit or depletion. As such, achieving
an aesthetically desirable outcome can be elusive
when working with an insufficient amount of HA
filler. To draw an analogy, imagine filling a bal-
loon with water. To inflate the balloon to capac-
ity, a certain threshold volume of water is
required. If not filled enough, the balloon would
remain loose and saggy rather than becoming
taut and tight. The amount of water required to
fill the balloon in this case depends on the size of
the balloon, that is, the larger the balloon, the
more water that is needed. Likewise, the more
severe the volume deflation, the larger the amount
of filler that is required. Otherwise, contour irreg-
ularity would continue to persist (Fig. 3.15).
Significantly, however, it is a customary prac-
tice of many aesthetic clinics to charge patients
by the number of syringes used, which creates an
incentive for patients to demand minimum doses
in order to lower their costs. Injecting too little,
a
b
Fig. 5.6  (a) Unevenness after HA fller injection in the tear trough only without considering the lack of volume in the
anterior malar region below to support it. (b) After hyaluronidase injection
5  Complications

271
however, often leads to suboptimal outcomes
which the patient may attribute instead to faulty
placement. Patients should therefore be coun-
seled on the drawbacks of underfilling and be fur-
ther advised that when it comes to facial
volumization treatments the volume of injection
also matters. The bottom line should be to get
more, they may need more.
5.3.2
Inadequate Balance
Enumerated below are the key regions of the face
where the overcorrection can take its toll, though
the same cardinal principle holds true for practi-
cally any facial area treated with volumizing fill-
ers; that is, there can be too much of a good thing.
1. Overfilling the nasal dorsum can widen the
nose, creating the appearance of the Avatar
nose or a lion nose. Unlike nasal implants
carved and inserted to fit precisely onto the
patient’s nose, filler rhinoplasty consists of a
fluid gel-type material injected in the dorsum
to lift the overlying soft tissue from within.
However, given that the tight skin envelope of
the nose exerts as much downward pressure
on the liquid filler as the filler pushing upward,
excess volume placed with the  intention of
elevating the nasal dorsum may end up spread-
ing sideways, broadening the nose as a conse-
quence. For reference, the ratio between the
width of dorsum to the nasal base should be
0.6 or less  in men, and even smaller in a
female nose.
2. The canine fossa located lateral to the nasal
ala is a quintessential structure constituting a
natural curvature of the face. Regardless, in
all too many cases, overtreatment of the
canine fossa during nasolabial fold correction
tends to be a common occurrence (Fig. 5.5).
Note that volume should be restored only up
to a contour that looks natural. Completely
effacing the subtle concavity naturally created
by
the
canine
fossa
removes
three-­
dimensionality from the face, blows the malar
cheeks out of proportion, and in the extreme,
gives a monkey-like appearance to the face.
The absence of this vital structure on the face
of a monkey bears noting in this respect.
3. Overtreating the central forehead during fore-
head augmentation without addressing the lat-
eral forehead regions lying above the brows
can lead to an odd localized protrusion in the
middle of the forehead. Meanwhile, placing
too much volume across the entire expanse of
the forehead can produce a disproportionately
bulbous forehead resembling that of a
dolphin.
4. In patients with pronounced bilateral zygoma,
volume added only  in the medial malar to
address infraorbital hollowness may cause lat-
eral expansion of the cheeks as the injected
volume blends with the fullness already pres-
ent in the lateral zygomatic region. In such a
case, concurrently filling the submalar depres-
sion and/or  subzygomatic depressions (the
posterior cheek) can help to subdue the cheek-
bone prominence due to optic illlusion.
5. Overfilling the pretarsal roll should be
avoided as it may disrupt the balance and har-
mony of the eyes. Notably, an overly thick
pretarsal roll in patients with horizontally
short eye apertures can create a particularly
odd, worm-­like appearance (Fig. 4.31). Note
that the ideal thickness of the pretarsal roll is
within 30% of the length of the eye aperture
(see Sect. 4.5.2).
6. To prevent the appearance of overdone, duck-­
like lips following lip augmentation, no more
than 3 cc of filler should be injected in a single
session. In patients with a naturally protruded
upper lip, the practitioner may consider not
injecting the upper lip at all or injecting con-
servative amounts only in its lateral aspects
(Fig. 4.98).
5.3.3
Delayed Irregularity
As previously noted, the gradual appearance of
irregularity in the injected area over time is gen-
erally attributable to the subsequent clumping of
HA filler due to the surrounding muscle activity
or to the hydrophilic tendency of HA to attract
water and gain volume.
5.3  Posttreatment Contour Irregularity

272
5.3.3.1 Aggregation of Filler
Due to Muscle Contraction
HA is known for its excellent safety profile
involving minimum adverse reactions in the
body. Nonetheless, when placed in regions of
heavy facial animation, corresponding muscle
contractions may cause the filler to shift and
migrate from the implanted site, resulting in aes-
thetically displeasing bulges and irregularities.
Classic examples include HA filler placed in the
forehead, glabella, and the infraorbital regions.
The hyperactivity of frontalis or corrugator mus-
cles following forehead augmentation may create
subsequent dimples or indentations in the fore-
head, glabella, or above-brow areas. In severe
cases, a large visible V-shaped indentation may
develop across the glabella and the central fore-
head region, evoking the image of the classic ani-
mation character super robot Mazinger Z.
This occurs most commonly in patients who
rely heavily on the frontalis m. to lift the upper
eyelid due to a preexisting blepharoptosis, aging-­
related eyelid hooding, or other genetic factors.
In such patients, BoNT-A injection is required in
the forehead/and glabella regions both before and
regularly after forehead augmentation to relax
and minimize relevant muscle movement. The
same applies when undertaking glabella volu-
mization in patients with a hypertrophic corruga-
tor m; adjunctive BoNT injection to the corrugator
m. is required to prevent the migration and col-
lection of HA filler.
The infraorbital region is also significantly
impacted by surrounding muscle contractions.
Protrusion of the hypertrophic medial muscular
band of the orbicularis oculi m. during smiling is
a normal and common occurrence in Koreans,
found in as many as 50–60% of the population
(Fig. 4.37). In people presenting such traits, how-
ever, HA filler or fat graft injected in the antero-
medial malar may accentuate the appearance of
this bulge upon smiling. With repeated muscle
contraction, the filler may clump up and protrude
even when the face is at rest. In such a case,
adjunctive BoNT-A injection into the medial
band of the orbicularis oculi m. before and after
filler injection can help to avoid such
occurrences.
5.3.3.2 Postinjection Swelling of HA
Filler
Due to its hydrophilic nature, HA filler is known
to expand compared to its original volume within
2–4 weeks of placement [20] (Fig. 2.14). On the
upside, the propensity of HA filler to attract
water from surrounding tissues and become
voluminous contributes to increased longevity.
However, undesired swelling when placed in
areas of reduced dermal thickness such as the
delicate periorbital region is a countervailing
drawback.
The tear trough represents a key risk area in
this respect as well as the lower pretarsal region
where the thickening of pretarsal rolls due to the
swelling of HA may appear worm-like and
unnatural. The nasal bridge is also an area where
the skin is thin and where the water retention
property of HA can cause lateral expansion of
HA filler, resulting in an unnaturally thick bulky
nasal dorsum resembling a lion nose. In this
respect, I made a serendipitous discovery many
years ago in which I found that patients who rou-
tinely drank more than two liters of water per
day were more susceptible to this phenomenon. I
had a patient some 10 years ago who was treated
in her tear trough with HA, but had to have the
filler dissolved 2  weeks later due to excessive
swelling. It took three iterations of reversing and
reinjecting the HA filler to finally reach the
desired outcome, and it was at some later point
the patient conveyed to me that she made it a rule
to regularly drink at least two liters of water per
day.
Different types of HA fillers have different
water absorption capacity. Monophasic HA fill-
ers tend to demonstrate a higher water retention
capacity  compared with biphasic HA fillers.
According to one study, monophasic HA fillers
(Belotero®, Juvederm®) absorbed more water
than biphasic HA fillers (Restylane®, Yvoir®) and
demonstrated a greater incremental increase in
volume 2–4 weeks postinjection vis-a-vis the ini-
tial injection volume (Fig. 2.14). Accordingly,
biphasic HA filler is better suited for treating
delicate areas such as the tear trough and the
lower pretarsal region, as undesired bulging or
expansion of HA filler is minimized.
5  Complications

273
5.3.3.3 Different Durations of Effect by
Facial Region
The rate at which HA filler is metabolized by our
body’s enzyme depends on the amount of HA
filler injected. Assuming the HA filler was
injected in the form of a bolus, the injected vol-
ume would be the greatest at the center of the
bolus while displaying a gradual tapering toward
the peripheral aspects. Correspondingly, the
thicker, more robust volume concentrated at the
center is better able to withstand enzymatic bio-
degradation compared with the thinner peripheral
volume which dissipates more quickly with time.
A classic example is the HA filler placed in the
anteriormedial malar region. Here, most of the
peripheral volume would wear off within a space
of 1–2  years, leaving only the central portion,
reduced to the size of a button by this time, to
become visible in patients with thin skin and little
subcutaneous fat to cover it.
Likewise, HA filler injected superficially at
the dermal or subdermal level tends to last con-
siderably longer than the HA filler placed more
deeply in the subcutaneous fat or muscular layers
where it tends to break down more rapidly. For
example, the superficially placed filler in the tear
trough is generally well maintained for more than
a year while the HA filler concurrently placed at
the deep subcutaneous fat of the anterior malar
tends to degrade more substantially during the
same period. This may create an unnatural
“ledge” in the lid–cheek junction as the superfi-
cial filler in the tear trough sits by itself with no
structure to support it from below. To smoothen
the transition in this case, a more feasible
approach is to restore the lost volume in the ante-
rior malar rather than dissolve the filler in the tear
trough.
5.3.4
Solution: Administration
of Hyaluronidase
Temporary lumpiness from postinjection reactive
swelling is normal and to be expected during the
first week of treatment. However, lumps and
bumps continuing beyond the first 1–2  weeks
deserve prompt resolution as they would persist
for months if not years if left attended. While the
ideal approach would be to strategically fill in
areas of relative volume deficiency to even out
the surface contour, in some cases the height of
bump is such that this becomes impracticable. In
such situations, reversing the HA filler with hyal-
uronidase is the only remaining alternative.
For complete dissolution of HA filler, hyal-
uronidase diluted to 150 U/mL should be admin-
istered at double the dose of the injected HA
filler. For partial dissolution of a localized bump
hyaluronidase should be injected at a diluted con-
centration of 30–50 U/mL [20] and a dose equal
to the volume of the injected filler. Given the fluid
nature of hyaluronidase injection, it should be
noted that the actual pattern of HA dissolution
cannot be predicted with precision and that the
risk of over-dissolving or under-dissolving exists
in any case.
The use of a cannula is generally preferred
also for administering hyaluronidase to prevent
tissue trauma and bruising. However, a 30G nee-
dle may become the preferred option where the
body has formed a hard nodule or encapsulation
around the HA filler due to collagen stimulation.
Precaution must be taken when injecting
hyaluronidase, given its animal origin as aller-
gic reactions to hyaluronidase, including ery-
thema and edema, may continue for several
days. Prior allergy skin test on the patient’s
forearm is therefore strongly advised. Positive
testing requires intravenous injection of steroids
and antihistamine prior to the hyaluronidase
injection.
Hyaluronidase takes immediate effect and
completely dissolves the filler within hours of
injection [8]. Any reapplication of HA following
its reversal should preferably be undertaken after
1  day has elapsed. Considering that hyaluroni-
dase has a short half-life of several minutes, HA
filler may theoretically be injected back after 8 h
of administering hyaluronidase. That said, in my
clinical experience where I had HA filler dis-
solved in the morning and reapplied in the eve-
ning of the same day, I perceived that a certain
amount of the freshly applied filler was partially
affected by the lingering hyaluronidase (See the
Sect. 5.4).
5.3  Posttreatment Contour Irregularity

274
5.4
The Adequate Use
of Hyaluronidase
HA dominates the world market for injectable
fillers driven significantly by its excellent safety
profile as a natural constituent of the human soft
tissue that is well-tolerated by the body. That
aside, it can be said that the true beauty of HA
filler lies in its reversibility, the assurance that
results could be dissolved instantaneously if so
desired using hyaluronidase as the reversal agent.
In my earlier practice, I had once worked with
semi-permanent synthetic fillers such as poly-
acrylamide gel (PAAG)-based Aquamid® or
polymethylmethacrylate
(PMMA)-based
Artecoll® or collagen stimulators such as
Radiesse® which provided prolonged longevity.
However, after experiencing a few cases where I
was unable to assist patients who, due to fluctua-
tions in their facial dimensions from subsequent
weight gains, wished to have the filler removed
1–2  years posttreatment, I converted entirely
to using only HA fillers in my practice.
Contingencies may occur even in the most expe-
rienced hands, and for the sake of ensuring peace
of mind as well as my own longevity (!), I opted
to use only fully reversible HA fillers.
In volumizing HA filler treatments, hyaluroni-
dase is commonly used to treat overcorrection or
unevenness from HA filler placement. Temporary
lumpiness from immediate postinjection swell-
ing is normal and to be expected during the first
week of treatment. However, lumps and bumps
persisting beyond the initial 1–2 weeks deserve
prompt resolution since they would persist for
months if not years if left addressed. The use of
hyaluronidase is also a critical step in responding
to vascular complications arising from emboliza-
tion by the HA filler, in which case hyaluronidase
should be injected to flush the occluded blood
vessel of the filler embolus. This chapter provides
specific details concerning the use of hyaluroni-
dase as the dissolving agent of HA, including the
pharmacological mechanism of action, the clini-
cal use of hyaluronidase for correcting HA filler
misplacement, the clinical use of hyaluronidase
for managing vascular complications, and poten-
tial
adverse
events
associated
with
its
administration.
5.4.1
Pharmacological
Characteristics
Hyaluronic acid, as a constituent of the body’s
extracellular matrix, plays a pivotal role in pro-
viding the tissue with the necessary structural
support, in modulating cellular migration and
proliferation, and in regulating inflammation and
wound repair/regeneration. In the human body,
50% of the native hyaluronic acid exists in the
skin, while the rest is present in various other
parts of the body such as the joints and the eyes.
Hyaluronic acid absorbs moisture in the tissues
to keep the tissue lubricated and hydrated while
providing it with structural support. Meanwhile,
as an enzyme, hyaluronidase is responsible for
breaking down the glucosaminidic bond between
C1 of the N-acetylglucosamine and C4 of the
d-glucuronic acid in the hyaluronic acid [22]. By
catalyzing the hydrolysis of the HA and effec-
tively breaking up the cellular linkages in the
interstitial tissue, hyaluronidase spurs the disper-
sion and absorption of injected drugs into the
interstitial tissue while promoting the resorption
of extravasated fluids back into the tissue.
Consequently, it is used clinically for hastening
the absorption of postsurgical hematoma or edema
in plastic surgery; for enhancing the diffusion and
permeation of drugs such as local anesthetics; and
also for hypodermoclysis, i.e.,  the subcutaneous
administration of fluid in conjunction with other
drugs in infants and elderly patients who are not
amenable to receiving an intravenous injection.
1 U of hyaluronidase is defined as the enzyme dos-
age discharged for degrading 1μmole of
N-acetylglucosamine at 37 °C pH 4 for 1 min [23].
The relevant dose/strength of  commercial hyal-
uronidases varies depending on manufacturers
from 150 to 2000 U (2000 U/vial) per vial, though
variations may exist between different products
and formulations. Six types of human hyaluroni-
dase have been reported in humans, including
HYAL-1, -2, -3, -4, HYALP1, and PH20.
5.4.2
Products (Fig. 5.7)
In the United States, bovine testicular hyaluron-
idase Hydase™ (PrimaPharm, Inc.), bovine tes-
5  Complications

275
ticular hyaluronidase Amphadase® (Amphastar
Pharmaceutical Inc.), ovine testicular hyaluron-
idase Vitrase® (ISTA Pharmaceutical), and
human recombinant DNA-derived hyaluroni-
dase
(r-HuPH20)
Hylenex®
(Halozyme
Therapeutics) have been approved for use.  In
Korea, there are more than 27 brands of hyal-
uronidase currently available on the market
including Hyalase® (Huons), BM Hylunidase®
(SH-Pharm), H-Lase® (Kuhnil Pharm), and
Hirax® (BMI Korea) with an identical product
marketed under the tradename PURIRAX® by
HanWha Pharma, all of which are derived from
bovine sources (Fig. 5.7) (Table 5.2). Incidence
of allergic reaction varies by formulation.
Among Korean products, notably, Hirax® (BMI
Korea) is a hyaluronidase preparation in inject-
able form which reportedly has achieved more
Fig. 5.7  Commercial hyaluronidase products
Table 5.2  Hyaluronidase products (available in the market)
Country
Brand name
Manufacturer
Type
Dose
Source
Korea
Hirax Injection 0.15%
BMIkorea
Solution
750IU/0.5 ml
2000IU/1.3 ml
1500IU/1 ml
5000IU/3.4 ml
Bovine
Korea
Purirax Inj
Hanwha Pharma Co,
Ltd.
Solution
1500IU/1 ml
Bovine
Korea
Liporase Inj.
DaehanNew Pharm Co,
Ltd.
Powder
1500 IU
Bovine
Korea
BM Hylunidase Inj.
BMIkorea
Powder
1500 IU
Bovine
Korea
Hyalase Inj.
Huons. Co, Ltd.
Powder
1500 IU
Bovine
USA
Vitrase
Bausch&Lomb
incorporated
Solution
200 IU
Ovine (sheep)
USA
Hylenex recombinant
Halozyme
Therapeutics, Inc.
Solution
150 IU
rHuPH20
(recombinant human
hyaluronidase)
Germany
Hyalase Dessau
Riemser Pharma
GmbH
Powder
150 IU
300 IU
Bovine
Ireland
Hyalase
Wockhardt UK Limited
Powder
1500 IU
Ovine
Spain
Reductonidasa
Mesoestetic Pharma
Solution
1500 IU
Bovine
Brazil
Hyaluronidase 2000
Biometil Swiss
Powder
2000 IU
Bovine
5.4  The Adequate Use of Hyaluronidase

276
than 95% purity and hence a dramatic reduction
in allergic reactions arising from extraneous
impurities remaining in the product. Except for
Vitrase®, Hylenex® and Hirax® supplied as a liq-
uid formulation, all others are available in the
form of powder for injection which require
reconstitution with normal saline. Upon recon-
stitution, the product must be stored at refrigera-
tion and used preferably within 10 hours
considering its loss of potency over time.
Hirax®, as an injectable solution, should be
stored at refrigeration while the other powder
formulatons should be kept at temperatures of
25 ˚C or below.Due to their animal origin, prod-
ucts derived either from bovine or ovine sources
may contain remnants of protein impurities
remaining in the product, which may trigger
undesired immunogenic responses. Incidence of
allergic reaction varies by product. Notably,
Hirax® (BMI Korea) as an injectable solution
has reportedly achieved more than 95% purity
and hence a dramatic reduction in allergic reac-
tions arising from any extraneous impurities
remaining in the product.
5.4.3
Use of Hyaluronidase
in the Correction of HA Filler
Placement (Table 5.3)
5.4.3.1 Dilution and Concentration of
Hyaluronidase
Most commercial hyaluronidase products  in
Korea are available in the form of powder for
solution contained in 1500 U/mL vials. Hence,
they must be reconstituted with an adequate
amount of saline solution. The pertinent concen-
tration of hyaluronidase to be used for dissolving
HA filler is open to debate. At the very least,
however, it should reasonably be higher than the
15 U/mL concentration indicated for facilitating
retrobulbar anesthesia in ophthalmic surgery to
ensure minimum impact on the vitreous body of
the eyeball.
While a hyaluronidase concentration of 20 U/
mL is described as sufficient for reversing HA
according to a prospective controlled study of dis-
solution of HA placed in the human dorsum, my
preferred concentration for completely dissolving
the HA filler is 150 U/mL [24]. The concentration
of 20–30  U/mL described in the study  may be
entirely valid for making partial corrections as a
higher dose of 50 U/mL, in my experience, tends
to degrade not only the excess amount of HA but
also HA placed in adjacent areas (Fig. 5.8). That
said, a higher concentration of 150 U/mL is clini-
cally preferable for the complete removal of HA,
as it delivers full resolution in a single session. For
Table 5.3  Recommended use of hyaluronidase for filler procedure
Indication
Concentration of
hyaluronidase
Volume of hyaluronidase
Needle vs
Cannula
Partial dissolution
Tiny bumps in upper eyelid,
and tear trough
20–50 U/mL
0.1–0.3 mL
Cannula
Overcorrection or
irregularity in the cheeks
20–50 U/mL
0.5–1 mL depending on the size
of correction
Cannula
Complete
dissolution
Overcorrection
150 U/mL
Hyaluronidase corresponding to
at least 2–3 times the volume of
the injected filler is required
Cannula
Round, palpable
encapsulations
150 U/mL
0.5–1 mL
Needle
Where previous attempts at
dissolution have proved
unsatisfactory
1500 U/mL
1–2 mL
Needle
Inflammation
150 U/mL
2–4 mL per site
Cannula
Vascular
complications
Intravascular embolization
750 U/mL
3–6 mL
Needle
Blindness
1500 U/mL
3–6 mL
Cannula
5  Complications

277
partial removal of HA filler, I inject small doses of
hyaluronidase at a reduced concentration of
20–50 U/mL to minimize the impact on the adja-
cent volume. On the other hand, where the HA
filler had proven to be resistant to dissolution with
hyaluronidase, I use a ten times higher concentra-
tion 1500 U/mL by reconstituting hyaluronidase
into a 1 mL solution.
5.4.3.2 Injection Dosage
of Hyaluronidase
The dosing of hyaluronidase for HA dissolution
varies according to the specific indication. To
completely dissolve the filler, hyaluronidase
(150 U/mL) corresponding to at least 2–3 times
the volume of the injected filler is administered.
Where the exact volume of the injected filler
cannot be determined, 2–4 mL (300–600 U) of
hyaluronidase per site is advised as a general
rule of thumb. For partial dissolution, hyaluroni-
dase should be injected at both reduced doses
and lower concentrations. Hyaluronidase dosage
is also adjusted according to the size of the area
and the overcorrection to be treated. For exam-
ple, for fine corrections of tiny bumps in small
areas such as the pretarsal roll, upper eyelid, and
tear trough, 0.1–0.3 mL of hyaluronidase diluted
to 20–50 ­U/mL is advised according to the size
of the bump. On the other hand, when addressing
overcorrection or irregularities in larger areas
such as the cheeks, a higher dose of 0.5–1 mL is
advisable depending on the size of excess vol-
ume injected. Gentle massage with fingers on the
injected site helps to dissolve the HA and imme-
diate dissolution of HA can be felt by palpation.
5.4.3.3 Cannula vs. Needle
The use of a cannula is preferred to prevent the risk
of bruising while delivering hyaluronidase. That
notwithstanding, the use of a 30G needle is advised
for piercing and dissolving round, palpable encap-
sulations, or where previous attempts at dissolu-
tion have proved unsatisfactory, or otherwise
where granuloma or scar-like hardness is present.
a
b
Fig. 5.8  Disfiguring irregularities caused by inappropri-
ate HA filler injection, thread lifting and liposuction was
improved using the combined treatment involving hyal-
urodiase for addressing the lumpiness in the pretarsal roll
and tear trough, and filler for restoring the depressed area
5.4  The Adequate Use of Hyaluronidase

278
5.4.3.4 Timing of HA Filler Reinjection
Most patients wish to have their HA filler redone
following the dissolution of the problematic HA
with hyaluronidase. In this respect, the optimal
timing of HA filler reinjection becomes an issue,
given concerns over the lingering impact of hyal-
uronidase. Views are divided on this point, with
some suggesting an interval of 2–3 days before
HA reinjection and others describing a much lon-
ger timeframe of 2–4 weeks to avoid the action of
residual hyaluronidase. However, given the short
half-life of hyaluronidase, HA filler may safely
be injected back 1 day after the injection of hyal-
uronidase. This is corroborated by the findings of
a rat study, which shows HA filler reinjected in
rats 6  hrs after dissolution with hyaluronidase
managed to substantially regain most of the pre-
vious shape and volume [25].
Certainly, in my own clinical experience where
I regularly dissolve and reinject HA filler in more
than 3–4 patients per day, I have never encoun-
tered any issues when HA filler was replaced the
day after its dissolution with hyaluronidase. Even
in the one isolated case where the filler was dis-
solved in the morning and reapplied 8 h later in
the evening due to the patient’s scheduled depar-
ture the following day, I merely perceived a
smaller-than-expected volume  augmentation at
follow-up. Conceivably, this suggests HA filler
may be reinjected as early as 6  h following its
reversal in certain inexplicable circumstances.
5.4.3.5 Reinjection of Hyaluronidase
Given the short half life of hyaluronidase which
lasts for only a few minutes in blood, the injec-
tion may be repeated 5 minutes after the first
injection if residual amounts of HA filler is pal-
pated.  Occasionally, the patient may request
reinjection of hyaluronidase following the ini-
tial administration, stating that the underlying
HA filler had not been fully dissolved. Indeed,
in some cases, residual amounts of HA filler
may be palpated upon physical examination. In
other cases, the problematic HA may no longer
be palpable contrary to the patient’s belief.
Reinjection of hyaluronidase generally follows
the same approach as the initial injection,
except where any soft encapsulations or hard
nodules can be felt, in which case a needle
should be used for performing the injection,
with the relevant dose upscaled to 750  U/
mL. Occasionally, even after the reinjection of
hyaluronidase and despite the absence of pal-
pable lumps, the patient may remain uncon-
vinced that the filler had been effectively
removed, requesting repeat treatment for the
third or fourth round. In other cases, what may
initially have been perceived as a hard nodule
from the  HA injection may turn out to have
been a previous fat graft or Sculptra. To avoid
further doubt and to spare the need for unneces-
sary intervention, it may be helpful to use ultra-
sonic devices to conclusively establish the
presence or absence of any lingering HA filler
in the tissue (see Sect. 5.4.8).
5.4.4
Use of Hyaluronidase
for Managing Inflammation
from Delayed-type
Hypersensitivity to HA or
Bacterial Infection
Though rare, acute inflammation may occur from
bacterial infection during HA filler treatment,
calling for the immediate removal of the product.
Also, in the rare case where the patient develops
delayed-type hypersensitivity to the cross-linking
agent BDDE or trace impurities such as the resid-
ual bacterial protein, DNA, or the intracellular
organelle not fully removed during the HA filler
manufacturing process, the underlying filler may
need to be removed (see Sect. 5.3). Here, suffi-
cient dosing of hyaluronidase 150 U/mL injected
at doses of 2–4 mL per site (i.e., 300–600 U in
total) is advised to achieve complete degradation
of the HA filler.
5.4.5
Use of Hyaluronidase
in the Treatment of Vascular
Complications from HA Filler
Injection
In the event of a vascular embolization due to
intravascular filler injection or vascular insuffi-
5  Complications

279
ciency from the compression of weak vessels by
the surrounding HA filler, the HA filler at issue
must immediately be dissolved away with hyal-
uronidase. While it is next to impossible to inject
hyaluronidase into the precise location in the ves-
sel where the occlusion is present, it has been pos-
tulated by Di Lorenzi et  al. that hyaluronidase
infused in sufficient amounts generally around the
area where ischemic symptoms are present may
effectively traverse and diffuse across the arterial
wall to reach the hyaluronic acid held in the blood
vessel. Hence, in order to dissolve occlusions of
hyaluronic acid fillers, it is advised to infiltrate
hyaluronidase subcutaneously in copious amounts
(3–6  mL) at a high concentration (750  U/mL)
around the tissue where ischemic symptoms such
as blanching, greyish decolorization, or mottled
erythema are  present. The effective timing of
hyaluronidase injection for such vascular events is
within 24 hrs of HA filler injection. This is also
backed up by the findings of an animal study in
which vascular occlusion was induced in rabbit
ears using HA filler, to which hyaluronidase was
subsequently injected at different intervals. While
hyaluronidase injected within 4 hrs was beneficial
in clearing the occlusion, it had little effect after
24  hours. Accordingly, patients demonstrating
even the slightest signs of ischemia should be
observed for 20–30 mins in the office for any fur-
ther development of symptoms. Progression of
symptoms calls for immediate injection of hyal-
uronidase for an effective resolution. Regardless,
there may still be some value to giving hyaluroni-
dase injections even after the 24-hour window as
a placebo for the patient, while protecting the
practitioner from the legal consequences of deny-
ing such intervention.
5.4.6
Allergic Reaction to
Hyaluronidase and Allergy
Testing
Allergic reaction to hyaluronidase injection may
be caused either by the enzyme itself or by other
extraneous protein impurities in the product as
most commercial hyaluronidase products consist
of protein derived from bovine or ovine testicular
tissue. The reported incidence of allergic reac-
tions to hyaluronidase varies widely, ranging
from 0.1% to 7%, depending on the product. The
vast majority of these reactions are antibody-­
mediated Type 1 hypersensitivity reactions with
typical symptoms being angioedema with severe
erythema and edema, or, in more serious situa-
tions, anaphylaxis. Though rare, the onset of
symptoms may start hours from the exposure to
hyaluronidase or even on the next day. While
occurring primarily in patients who have previ-
ously been treated with hyaluronidase for dis-
solving
HA
filler,
allergic
reactions
to
hyaluronidase may occur even upon the first
exposure independent of such treatment history.
In those without a prior history of hyaluronidase
injection, allergic reactions may occur instead as
a result of an allergy to bovine protein or even
from a previous bee venom therapy, given that
hyaluronidase is also found in fire ants, bees, and
arthropods such as scorpions.
Alternatively, the patient may have been
unknowingly sensitized to hyaluronidase by
receiving fat dissolving injections or facial con-
touring injections from aesthetic clinics whose
proprietary formulations not disclosed to the
patient happened to contain hyaluronidase.
Simply put, allergies may develop irrespective of
previous hyaluronidase injections. As such, a pre-
liminary skin test must be performed as a matter
of course, to determine the presence of allergies in
patients wishing to undergo hyaluronidase treat-
ment. The skin test is undertaken by an intrader-
mal injection of 0.1  mL of 150  Unit/mL
hyaluronidase in the forearm. The development of
erythema or a red raised wheal with pseudopods
appearing within 15 min accompanied by local-
ized itching indicates a positive reaction (Fig. 5.9).
Note once again that, although rare, allergic
reactions may not appear until several hours
later, if not until the day following hyaluroni-
dase injection. Where the patient tests positive,
intravenous injection of dexamethasone (1
ampoule) combined with antihistamine Avil (1
ampoule) administered 10  min prior to hyal-
uronidase injection provides effective cover
against allergic reactions, if not reducing the
symptoms to a mild edema. Oral prednisolone
10 mg bid 8 mg for 2 days is also prescribed fol-
lowing treatment.
5.4  The Adequate Use of Hyaluronidase

280
Fig. 5.10  Skin atrophy deveoped on the forearm after
allergy testing for hyaluronidase
a
b
Fig. 5.9  The skin test for the hyaluronidase. (a)
Liporase®; positive, hylunidase®; positive, Hirax®; nega-
tive. (from the top to bottom). (b) The development of
erythema or a red raised wheal with pseudopods appear-
ing within 15 minutes accompanied by localized itching,
indicates a positive reaction
The incidence of allergic reaction varies by
product. Among Korean products, Hirax® (BMI
Korea), with identical product marketed under
the trade name PURIRAX® by HanWha Pharma
Co., Ltd., has shown a relatively lower inci-
dence of allergic reactions. Notably, Hirax®
(BMI Korea) is a hyaluronidase preparation in
injectable form, which reportedly demonstrates
more than 95% purity and results in a dramatic
reduction in allergic reactions arising from
impurities.
5.4.7
Skin Atrophy
Granted, hyaluronidase may dissolve the body’s
own native hyaluronic acid in the skin or tissue
(Fig.  5.10). Significantly, hyaluronidase injec-
tion made directly into the dermis is highly likely
to induce skin atrophy, given that more than 50%
5  Complications

281
of the body’s naturally occurring hyaluronic acid
is present in the skin (Fig.  5.11). By contrast,
hyaluronidase injected in the subcutaneous fat
will not cause any visible deformities or atrophic
indentations on the skin surface since the level of
hyaluronic acid contained in the subcutaneous
fatty layer is much lower by default. In my prac-
tice, I regularly inject hyaluronidase subcutane-
ously to dissolve HA filler at doses as high as
300–600 U. Yet, I have never encountered any
noticeable skin atrophy or tissue deformation in
my patients, even though I typically handle more
than 3–4 such cases on any given day. Even
when hyaluronidase is injected in the dermis, it
will not cause long-term detriment to the skin, as
the body substantially replenishes the native
hyaluronic acid within 2  weeks, allowing the
skin to naturally regains its normal integrity
within 1 month.
5.4.8
Use of Ultrasonic Imaging
to Establish the Presence
of HA in the Tissue
In ultrasonic scans, HA is easily distinguished
from other tissues since it consists of 99% water
and appears anechoic (black) on ultrasound image
(Fig. 5.12). Therefore, the use of ultrasound can
be instrumental in locating the HA filler before
its dissolution or establishing the specific nature
of the material in question, that is, whether it con-
sists of dissolvable HA filler or any other sub-
stance (Fig. 5.13).
Fig. 5.11  Multiple atrophied depressions in face devel-
oped after intradermal injection of hyaluronidase with the
concentration of 500 U/ml
HA filler
a
b
Fig. 5.12  (a) Small nodules are observed 1 year after HA filler injection for the treatment of marrionett lines.
(b) Two round anechoi nodules are observed by ultrasound evaluation
5.4  The Adequate Use of Hyaluronidase

282
References
1. Kim HJ, Kyle Seo HK, Lee JS. Kim. In: Clinical anat-
omy for botulinum toxin and filler injection. Berlin:
Springer; 2016.
2. Beleznay K, Jones D.  Vascular compromise. In:
Carruthers J, Carruthers A, editors. Soft tissue aug-
mentation. Philadelphia: Elsevier; 2018. p. 185–9.
3. Bolton JG, Fabi SG.  Complications of Temporary
Fillers. In: Carruthers J, Carruthers A, editors. Soft
tissue augmentation. Philadelphia: Elsevier; 2018.
p. 191–201.
4. DeLorenzi C.  Complications of injectable fill-
ers, part 2: vascular complications. Aesthet Surg J.
2014;34(4):584–600.
5. Kim DW, Yoon ES, Ji YH, Park SH, Lee BI, Dhong
ES. Vascular complications of hyaluronic acid fillers
and the role of hyaluronidase in management. J Plast
Reconstr Aesthet Surg. 2011;64:1590–5.
6. Beleznay K, JDA C, Humphrey S, Jones D. Avoiding
and treating blindness from fillers: a review of the
world literature. Dermatol Surg. 2015;41:1097–117.
7. Park KH, Kim YK, Woo SJ, Kang SW, Lee WK, Choi
KS, Kwak HW, Yoon H, Huh K, Kim JW. Iatrogenic
occlusion of the ophthalmic artery after cosmetic facial
filler injections a national survey by the Korean retina
society. JAMA Ophthalmol. 2014;132(6):714–23.
8. Casabona G, Montes JR, Marchese P. Reversers. In:
Carruthers J, Carruthers A, editors. Soft tissue aug-
mentation. Philadelphia: Elsevier; 2018. p. 215–26.
9. Zhu GZ, Sun ZS, Liao WX, Cai B, Chen CL, Zheng
HH, Zeng L, Luo SK. Efficacy of retrobulbar hyal-
uronidase injection for vision loss resulting from
hyaluronic acid filler embolization. Aesthet Surg J.
2017;38(1):12–22.
10. Surek CC, Said SA, Perry JD, Zins JE. Retrobulbar
injection for hyaluronic acid gel filler-induced
­blindness: a review of efficacy and technique. Aesthet
Plast Surg. 2019;43(4):1034–40.
11. Lee W, Oh W, Ko HS, Lee SY, Kim KW, Yang
EJ. Effectiveness of retrobulbar hyaluronidase injec-
tion in an iatrogenic blindness rabbit model using
hyaluronic acid filler injection. Plast Reconstr Surg.
2019;144(1):137–43.
12. Parness G, Underhill S. Regional anesthesia for intra-
ocular surgery. Contin Educ Anaesth Crit Care Pain.
2005;5(3):93–7.
13. Kumar CM, Eid H, Dodds C. Sub-­Tenon’s anaesthe-
sia: complications and their prevention. Eye (Lond).
2011;25(6):694–703.
14. Gell PGH, Coombs RRA, editors. Clinical aspects
of immunology. 1st ed. Oxford, England: Blackwell;
1963.
15. Ahn JS. J Korean Soc Dermatol Surg. 2017;4:41–7.
16. Alijotas-Reig J, Garcia-Gimenez V. Delayed immune-­
mediated complications related to hyaluronic acid and
acrylic hydrogel dermal fillers: clinical findings, long-­
term follow-up, and review of the literature. J Eur
Acad Dermatol Venereol. 2008;22(2):150–61.
17. Roh NK. The things filler manufacturers won’t let you
know. Filler Toxin. 2018;2018:31–4.
18. Friedman PM, Mafong EA, Kauvar AN, Geronemus
RG.  Safety data of injectable nonanimal stabilized
hyaluronic acid gel for soft tissue augmentation.
Dermatol Surg. 2002;28:491–4.
19. Beleznay K, Carruthers JD, Carruthers A, et  al.
Delayed-onset nodules secondary to a smooth, cohe-
sive 20mg/ml hyaluronic acid filler: cause and man-
agement. Dermatol Surg. 2015;41(8):929–39.
20. Park KY, Kim JM, Seok J, Seo SJ, Kim MN, Youn
CS.  Comparative split-face study of durational
a
b
Fig. 5.13  (a) Irregularity cuased by Sculptra® injection into the infraorbital depression. (b) Hyperechoic masses are
observed by ultrasound evaluation
5  Complications

283
changes in hyaluronic acid fillers for mid-face volume
augmentation. Dermatol Ther. 2019;32(4):e12950.

21. Juhász MLW, Levin MK, Marmur ES. The kinetics of
reversible hyaluronic acid filler injection treated with
hyaluronidase. Dermatol Surg. 2017;43(6):841–7.
22. Ferraz RM, Sandkvist U, Lundgren B.  Degradation
of hylauronic acid fillers using hyaluronidase in an
in vivo model. J Drugs Dermatol. 2018;17(5):548–53.
23. Dunn AL, et al. Hyaluronidase: a review of approved
formulations, indications and off-label use in
chronic pain management. Expert Opin Biol Ther.
2010;10(1):127–31.
24. Margit LW Juhász, Melissa K Levin, Ellen S Marmur.
The Kinetics of Reversible Hyaluronic Acid Filler
Injection Treated With Hyaluronidase Dermatol Surg.
2017;43(6):841–7.
25. Kim HJ, Kwon SB, Whang KU, Lee JS, Park YL,
Lee SY. The duration of hyaluronidase and optimal
timing of hyaluronic acid (HA) filler reinjection
after hyaluronidase injection. J Cosmet Laser Ther.
2018;20(1):52–7.
References